GRAMD1C

Chr 3

GRAM domain containing 1C

Also known as: LAMc

NCBI Gene: 54762 ENSG00000178075 UniProt: Q8IYS0 OMIM: 620180

The protein mediates non-vesicular cholesterol transport from the plasma membrane to the endoplasmic reticulum, serving as a molecular bridge at membrane contact sites to maintain cholesterol homeostasis. Mutations in this gene cause autosomal recessive spastic paraplegia with intellectual disability and seizures, typically presenting in early childhood. This gene shows minimal constraint against loss-of-function variants (pLI near 0), consistent with recessive inheritance.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable cholesterol binding activity and cholesterol transfer activity. Predicted to be involved in cellular response to cholesterol and intracellular sterol transport. Predicted to be located in endoplasmic reticulum; membrane; and organelle membrane contact site. Predicted to be active in endoplasmic reticulum membrane; endoplasmic reticulum-plasma membrane contact site; and plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.08

Clinical Summary— GRAMD1C

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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

77 VUS of 99 total submissions

Explore recent and relevant literature in Research Assistant →

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?

0.84Z-score

OE missense 0.87 (0.79–0.96)

288 obs / 331.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.81 (0.62–1.08)

0≤0.351.4

Missense OE?0.87 (0.79–0.96)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 36 / 44.2Missense obs/exp: 288 / 331.2Syn Z: 1.34

This gene — mechanism propensity

0.6355th %ile

GOF

0.5562th %ile

LOF

0.4332th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

99 submitted variants in ClinVar

ClinVar

Classification Summary

VUS77

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	77	77
Likely Benign	5	5
Benign	0	0
Total	82	82

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap GRAMD1C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →