Is EFEMP2 p.Arg427Gln (c.1280G>A) pathogenic?

EFEMP2 p.Arg427Gln (c.1280G>A) is classified Uncertain significance in EFEMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-11). AlphaMissense: likely benign (0.2864); Ultra-rare (popmax 0.0117%, amr); Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.Arg427Gln (c.1280G>A)?

EFEMP2 p.Arg427Gln (c.1280G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EFEMP2 p.Arg427Gln (c.1280G>A) in the general population?

EFEMP2 p.Arg427Gln (c.1280G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about EFEMP2 p.Arg427Gln (c.1280G>A)?

AlphaMissense predicts likely benign (score 0.2864) — an in-silico prediction, not a clinical call.

EFEMP2 p.Arg427Gln

c.1280G>A · rs766995796 · VCV1767857

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2864 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2864	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -5.11	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 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 5,433 bp · p 3.8e-05 · regional, not allelic
Overall
CADD	24.9	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 0.0117% Admixed American · 7/60,004 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.0013% 21/1,614,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,572
South Asian	0.00439%	22,772
African / African-American	0.00133%	74,926
European (non-Finnish)	0.000763%	131,115

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.Arg427Gln
Coding: c.1280G>A
MANE Select: NM_016938
dbSNP: rs766995796
Type: single nucleotide variant
Location: chr11:65866970 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB

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.Arg427Trp 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
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-arg427gln (accessed [today's date]).

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