Is EFEMP2 p.Val316Met (c.946G>A) pathogenic?

EFEMP2 p.Val316Met (c.946G>A) is classified Uncertain significance in EFEMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-01). AlphaMissense: likely benign (0.1116); Ultra-rare (popmax 0.0164%, mid); Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.Val316Met (c.946G>A)?

EFEMP2 p.Val316Met (c.946G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EFEMP2 p.Val316Met (c.946G>A) in the general population?

EFEMP2 p.Val316Met (c.946G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about EFEMP2 p.Val316Met (c.946G>A)?

AlphaMissense predicts likely benign (score 0.1116) — an in-silico prediction, not a clinical call.

EFEMP2 p.Val316Met

c.946G>A · rs113167523 · VCV3226940

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1116 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1116	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -8.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.66, phastCons 0.98
Regional constraint	o/e 0.83	unconstrained · MANE · 5,433 bp · p 3.8e-05 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00124% 20/1,613,646 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,452
European (non-Finnish)	0.00127%	78,669

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EFEMP2
Protein: p.Val316Met
Coding: c.946G>A
MANE Select: NM_016938
dbSNP: rs113167523
Type: single nucleotide variant
Location: chr11:65868323 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB
Residue 316: a disulfide bond; the egf-like 6; calcium-binding domain

Full EFEMP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EFEMP2 p.Val316Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
EFEMP2 p.Glu167Ter Pathogenic ★★ same condition
EFEMP2 c.608-3C>G Uncertain significance ★★ same condition
EFEMP2 p.Ala103Thr Uncertain significance ★★ ⚠ same condition
EFEMP2 p.Ala291Gly Uncertain significance ★★ ⚠ same condition
EFEMP2 p.Ala85Thr Uncertain significance ★★ ⚠ same condition
EFEMP2 p.Ala86Thr Uncertain significance ★★ ⚠ same condition
EFEMP2 p.Arg156Cys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/efemp2-p-val316met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown