Is EFEMP2 p.Ile165Val (c.493A>G) pathogenic?

EFEMP2 p.Ile165Val (c.493A>G) is classified Uncertain significance in EFEMP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-19). AlphaMissense: likely benign (0.2595); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.Ile165Val (c.493A>G)?

EFEMP2 p.Ile165Val (c.493A>G) is associated with Cardiovascular phenotype, cutis laxa, autosomal recessive, type 1B (ClinVar).

How common is EFEMP2 p.Ile165Val (c.493A>G) in the general population?

EFEMP2 p.Ile165Val (c.493A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EFEMP2 p.Ile165Val (c.493A>G)?

AlphaMissense predicts likely benign (score 0.2595) — an in-silico prediction, not a clinical call.

EFEMP2 p.Ile165Val

c.493A>G · rs1859941615 · VCV1490958

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2595 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2595	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -5.98	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 1.5	GERP 0.91, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 5,433 bp · p 3.8e-05 · regional, not allelic
Overall
CADD	17.72	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EFEMP2
Protein: p.Ile165Val
Coding: c.493A>G
MANE Select: NM_016938
dbSNP: rs1859941615
Type: single nucleotide variant
Location: chr11:65870235 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB
Residue 165: 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

Also linked: cutis laxa, autosomal recessive, type 1B

Similar variants

EFEMP2 p.Arg279Cys Likely pathogenic ★★ same condition
EFEMP2 p.Asp203Ala Pathogenic/Likely pathogenic ★★ same condition
EFEMP2 p.Glu126Lys Pathogenic/Likely pathogenic ★★ same condition
EFEMP2 p.Glu161Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
EFEMP2 p.Glu167Ter Pathogenic ★★ same condition
EFEMP2 c.161-6C>G Uncertain significance ★★ same condition
EFEMP2 c.491-5C>G Uncertain significance ★★ same condition
EFEMP2 c.608-3C>G 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-ile165val (accessed [today's date]).

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