GRAMD4

Chr 22

GRAM domain containing 4

Also known as: DIP

NCBI Gene: 23151 ENSG00000075240 UniProt: Q6IC98 OMIM: 613691

GRAMD4 encodes a mitochondrial protein that mediates E2F1-induced apoptosis and regulates TLR9-mediated innate immune responses. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.16), suggesting that mutations would likely cause severe disease, though no specific genetic disorder has been established yet. This makes GRAMD4 a candidate gene for neurodevelopmental or metabolic disorders when identified in patients with unexplained phenotypes.

OMIM ResearchSummary from RefSeq, UniProt

GRAMD4 is a mitochondrial effector of E2F1 (MIM 189971)-induced apoptosis (Stanelle et al., 2005 [PubMed 15565177]).[supplied by OMIM, Jan 2011]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.16

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 5.48

OE 0.05 (0.02–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.56Z-score

OE missense 0.64 (0.57–0.71)

249 obs / 391.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.16)

0≤0.351.4

Missense OE?0.64 (0.57–0.71)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 2 / 38.8Missense obs/exp: 249 / 391.3Syn Z: 0.02

Background carrier burden — how many people carry a rare variant somewhere in GRAMD4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 90

667 rare PASS variants

Rare truncating (LoF)

1 in 6,200

52 rare PASS variants

Rare synonymous (reference)

1 in 87

370 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GRAMD4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 8,500
South Asian	~43k	1 in 60	1 in 4,900
Remaining (unassigned)	~30k	1 in 120	none seen
European (Finnish)	~27k	1 in 550	1 in 4,300
Admixed American	~22k	1 in 88	≈ 1 in 7,700
African / African American	~21k	1 in 120	≈ 1 in 9,300
East Asian	~20k	1 in 110	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 480	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 110	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.