Is EFEMP1 p.Val253Ile (c.757G>A) pathogenic?

EFEMP1 p.Val253Ile (c.757G>A) is classified Conflicting classifications of pathogenicity in EFEMP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-26). AlphaMissense: likely benign (0.0917); Ultra-rare (popmax 0.0121%, sas).

How common is EFEMP1 p.Val253Ile (c.757G>A) in the general population?

EFEMP1 p.Val253Ile (c.757G>A) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about EFEMP1 p.Val253Ile (c.757G>A)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

EFEMP1 p.Val253Ile

c.757G>A · rs142542256 · VCV1982446

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -6.70	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 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 51 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/91,074 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00217% 35/1,612,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,279
African / African-American	0.004%	24,989
Admixed American	0.00334%	29,977
East Asian	0.00223%	44,834
Remaining individualsnot grpmax-eligible	0.0016%	62,420
European (non-Finnish)	0.00144%	69,364

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: EFEMP1
Protein: p.Val253Ile
Coding: c.757G>A
MANE Select: NM_001039348
dbSNP: rs142542256
Type: single nucleotide variant
Location: chr2:55877749 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 253: a UniProt-annotated variant site (in arcl1d; likely pathogenic); the egf-like 3; calcium-binding domain

Full EFEMP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFEMP1 p.Val253Leu Uncertain significance ★ ⚠ same residue
EFEMP1 p.Arg345Trp Pathogenic/Likely pathogenic ★★ same type
EFEMP1 p.Ala104Thr Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala126Pro Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala126Thr Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala447Ser Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala447Thr Uncertain significance ★★ ⚠ same type
EFEMP1 p.Arg148His Uncertain significance ★★ ⚠ same type

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/efemp1-p-val253ile (accessed [today's date]).

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