Is EFEMP2 p.Arg53Trp (c.157C>T) pathogenic?

EFEMP2 p.Arg53Trp (c.157C>T) is classified Uncertain significance in EFEMP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-27). AlphaMissense: ambiguous (0.3933); Very rare (popmax 0.00733%, eas); Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.Arg53Trp (c.157C>T)?

EFEMP2 p.Arg53Trp (c.157C>T) is associated with Cardiovascular phenotype, cutis laxa, autosomal recessive, type 1B (ClinVar).

How common is EFEMP2 p.Arg53Trp (c.157C>T) in the general population?

EFEMP2 p.Arg53Trp (c.157C>T) is very rare (popmax 0.00733%, eas) (gnomAD).

What do computational predictors say about EFEMP2 p.Arg53Trp (c.157C>T)?

AlphaMissense predicts ambiguous (score 0.3933) — an in-silico prediction, not a clinical call.

EFEMP2 p.Arg53Trp

c.157C>T · rs936904481 · VCV1330731

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00733%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3933	ambiguous
REVEL	0.54	indeterminate
SaProt	LLR -11.60	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -0.75, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 5,433 bp · p 3.8e-05 · regional, not allelic
Overall
CADD	27.5	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 0.00733% East Asian · 3/40,920 alleles

Filtering AF 0.00194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00136% 19/1,399,368 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00733%	13,640
Remaining individualsnot grpmax-eligible	0.00333%	30,061
European (non-Finnish)	0.00122%	81,924

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.Arg53Trp
Coding: c.157C>T
MANE Select: NM_016938
dbSNP: rs936904481
Type: single nucleotide variant
Location: chr11:65871973 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB
Residue 53: the egf-like 1; atypical 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.Arg53Gln Uncertain significance ★★ ⚠ same residue
EFEMP2 p.Arg53Gly Uncertain significance ★ same residue
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

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-arg53trp (accessed [today's date]).

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