Is EFEMP2 p.Ala428Val (c.1283C>T) pathogenic?

EFEMP2 p.Ala428Val (c.1283C>T) is classified Uncertain significance in EFEMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-25). AlphaMissense: ambiguous (0.4843); Very rare (popmax 0.00223%, eas); Associated with cutis laxa, autosomal recessive, type 1B.

What condition is associated with EFEMP2 p.Ala428Val (c.1283C>T)?

EFEMP2 p.Ala428Val (c.1283C>T) is associated with cutis laxa, autosomal recessive, type 1B (ClinVar).

How common is EFEMP2 p.Ala428Val (c.1283C>T) in the general population?

EFEMP2 p.Ala428Val (c.1283C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Autosomal recessive cutis laxa type 1 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EFEMP2 p.Ala428Val (c.1283C>T)?

AlphaMissense predicts ambiguous (score 0.4843) — an in-silico prediction, not a clinical call.

EFEMP2 p.Ala428Val

c.1283C>T · rs1565272014 · VCV581860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4843 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

cutis laxa, autosomal recessive, type 1B

Computational evidence

Protein change
AlphaMissense	0.4843	ambiguous
REVEL	0.333	indeterminate
SaProt	LLR -8.55	tolerated
Splicing
SpliceAI	—	not looked up on this page · why
Pangolin	Δ0.46	gain · loss 0.00 · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 0.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 5,433 bp · p 3.8e-05 · regional, not allelic
Overall
CADD	29.9	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 0.00223% East Asian · 1/44,886 alleles

Overall 6.84e-05% 1/1,461,874 alleles · very rare

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.Ala428Val
Coding: c.1283C>T
MANE Select: NM_025128 · reported on NM_016938
dbSNP: rs1565272014
Type: single nucleotide variant
Location: chr11:65866967 (GRCh38)

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

Disease context

cutis laxa, autosomal recessive, type 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive cutis laxa type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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-ala428val (accessed [today's date]).

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