Is EFEMP2 p.Arg53Gln (c.158G>A) pathogenic?

EFEMP2 p.Arg53Gln (c.158G>A) is classified Uncertain significance in EFEMP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-27). AlphaMissense: likely benign (0.0983); Very rare (popmax 0.00411%, afr); Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.Arg53Gln (c.158G>A)?

EFEMP2 p.Arg53Gln (c.158G>A) is associated with Cardiovascular phenotype, cutis laxa, autosomal recessive, type 1B, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is EFEMP2 p.Arg53Gln (c.158G>A) in the general population?

EFEMP2 p.Arg53Gln (c.158G>A) is very rare (popmax 0.00411%, afr) (gnomAD).

What do computational predictors say about EFEMP2 p.Arg53Gln (c.158G>A)?

AlphaMissense predicts likely benign (score 0.0983) — an in-silico prediction, not a clinical call.

EFEMP2 p.Arg53Gln

c.158G>A · rs372018326 · VCV1056034

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00411%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0983	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.63, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 5,433 bp · p 3.8e-05 · regional, not allelic
Overall
CADD	25.0	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 0.00411% African / African-American · 3/73,010 alleles

Filtering AF 0.00158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00206% 32/1,551,494 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00698%	14,327
African / African-Americangrpmax	0.00411%	24,337
European (non-Finnish)	0.00227%	44,114
Remaining individualsnot grpmax-eligible	0.00166%	60,098

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg53Gln
Coding: c.158G>A
MANE Select: NM_016938
dbSNP: rs372018326
Type: single nucleotide variant
Location: chr11:65871972 (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 familial thoracic aortic aneurysm and aortic dissection

Similar variants

EFEMP2 p.Arg53Trp 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-arg53gln (accessed [today's date]).

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