MFSD8

Chr 4AR

major facilitator superfamily domain containing 8

Also known as: CCMD, CLN7, SLC74A1

NCBI Gene: 256471 ENSG00000164073 OMIM: 611124

The encoded protein functions as an outward-rectifying chloride channel that maintains endolysosomal chloride homeostasis, regulates lysosomal calcium content by activating TRPML1 channels, and contributes to progressive acidification from endosome to lysosome. Mutations cause neuronal ceroid lipofuscinosis type 7 (variant late infantile-onset) and macular dystrophy with central cone involvement through an autosomal recessive inheritance pattern. Disease results from loss-of-function mutations that disrupt endolysosomal membrane function and ion homeostasis.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a ubiquitous integral membrane protein that contains a transporter domain and a major facilitator superfamily (MFS) domain. Other members of the major facilitator superfamily transport small solutes through chemiosmotic ion gradients. The substrate transported by this protein is unknown. The protein likely localizes to lysosomal membranes. Mutations in this gene are correlated with a variant form of late infantile-onset neuronal ceroid lipofuscinoses (vLINCL). [provided by RefSeq, Oct 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.072 OMIM phenotypes

Clinical Summary— MFSD8

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Gene-Disease Validity (ClinGen)

neuronal ceroid lipofuscinosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

185 unique Pathogenic / Likely Pathogenic· 384 VUS of 1061 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MFSD8

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.07LOEUF

pLI 0.000

Z-score 1.27

OE 0.75 (0.53–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.11Z-score

OE missense 0.98 (0.89–1.08)

275 obs / 280.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.75 (0.53–1.07)

0≤0.351.4

Missense OE?0.98 (0.89–1.08)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 22 / 29.5Missense obs/exp: 275 / 280.4Syn Z: -0.02

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMFSD8-related neuronal ceroid-lipofuscinosisLOFAR

Mechanism Note (expert annotation)

LOF

Lysosomal membrane transporter. Biallelic LOF causes CLN7 (variant late-infantile neuronal ceroid lipofuscinosis). This is an autosomal recessive LOF gene.1

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7229th %ile

GOF

0.6149th %ile

LOF

0.2874th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 17564974 ↗

ClinVar Variant Classifications

1061 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic91

Likely Pathogenic94

VUS384

Likely Benign401

Benign43

Conflicting37

Pathogenic

Likely Pathogenic

384

VUS

401

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	64	4	23	0	91
Likely Pathogenic	71	17	6	0	94
VUS	7	308	59	10	384
Likely Benign	0	5	181	215	401
Benign	0	1	41	1	43
Conflicting	—				37
Total	142	335	310	226	1,050

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

30 pathogenic / likely-pathogenic (of 42) ClinVar copy-number / structural variants overlap MFSD8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →