Is EFEMP2 p.Arg176Cys (c.526C>T) pathogenic?

EFEMP2 p.Arg176Cys (c.526C>T) is classified Uncertain significance in EFEMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely pathogenic (0.9433); Very rare (popmax 0.0022%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.Arg176Cys (c.526C>T)?

EFEMP2 p.Arg176Cys (c.526C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EFEMP2 p.Arg176Cys (c.526C>T) in the general population?

EFEMP2 p.Arg176Cys (c.526C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about EFEMP2 p.Arg176Cys (c.526C>T)?

AlphaMissense predicts likely pathogenic (score 0.9433) — an in-silico prediction, not a clinical call.

EFEMP2 p.Arg176Cys

c.526C>T · rs773297046 · VCV3226933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9433 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9433	likely pathogenic
REVEL	0.676	pathogenic-leaning
SaProt	LLR -13.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.72, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 5,433 bp · p 3.8e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0022% South Asian · 2/91,068 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000684% 10/1,461,410 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,534
European (non-Finnish)	0.000678%	147,497

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.Arg176Cys
Coding: c.526C>T
MANE Select: NM_016938
dbSNP: rs773297046
Type: single nucleotide variant
Location: chr11:65870202 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB
Residue 176: a disulfide bond; the egf-like 3; 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.Arg176His Uncertain significance ★★ ⚠ same residue
EFEMP2 p.Arg176Gly Uncertain significance ★ ⚠ 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

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-arg176cys (accessed [today's date]).

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