AFG2A

Chr 4

AAA ATPase AFG2A

Also known as: AFG2, EHLMRS, NEDHSB, SPAF, SPATA5

NCBI Gene: 166378 ENSG00000145375 UniProt: Q8NB90

AFG2A encodes an ATP-dependent chaperone that is part of a chromatin-associated complex essential for DNA replication fork progression, genome stability, and ribosomal particle maturation. Biallelic mutations cause a neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities with autosomal recessive inheritance. The gene shows very low constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed clinically.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the ATPase associated with diverse activities family, whose members are defined by a highly conserved ATPase domain. Members of this family participate in diverse cellular processes that include membrane fusion, DNA replication, microtubule severing, and protein degradation. The protein encoded by this gene has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Allelic variants in this gene have been associated with epilepsy, hearing loss, and cognitive disability syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.08

Clinical Summary— AFG2A

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Gene-Disease Validity (ClinGen)

syndromic complex neurodevelopmental disorder · 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

113 unique Pathogenic / Likely Pathogenic· 389 VUS of 930 total submissions

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.08LOEUF

pLI 0.000

Z-score 1.14

OE 0.81 (0.62–1.08)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.46Z-score

OE missense 0.94 (0.87–1.02)

446 obs / 474.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.81 (0.62–1.08)

0≤0.351.4

Missense OE?0.94 (0.87–1.02)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 34 / 42.0Missense obs/exp: 446 / 474.2Syn Z: 0.60

ClinVar Variant Classifications

930 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic64

Likely Pathogenic49

VUS389

Likely Benign337

Benign49

Conflicting29

Pathogenic

Likely Pathogenic

389

VUS

337

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	49	4	11	0	64
Likely Pathogenic	25	20	4	0	49
VUS	3	357	26	3	389
Likely Benign	1	5	137	194	337
Benign	0	5	40	4	49
Conflicting	—				29
Total	78	391	218	201	917

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap AFG2A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →