Is EFEMP2 p.Arg409Trp (c.1225C>T) pathogenic?

EFEMP2 p.Arg409Trp (c.1225C>T) is classified Uncertain significance in EFEMP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.4608); Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.Arg409Trp (c.1225C>T)?

EFEMP2 p.Arg409Trp (c.1225C>T) is associated with Cardiovascular phenotype, cutis laxa, autosomal recessive, type 1B (ClinVar).

How common is EFEMP2 p.Arg409Trp (c.1225C>T) in the general population?

EFEMP2 p.Arg409Trp (c.1225C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about EFEMP2 p.Arg409Trp (c.1225C>T)?

AlphaMissense predicts ambiguous (score 0.4608) — an in-silico prediction, not a clinical call.

EFEMP2 p.Arg409Trp

c.1225C>T · rs774325189 · VCV1493792

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4608 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Cardiovascular phenotype

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.4608	ambiguous
REVEL	0.58	indeterminate
SaProt	LLR -12.54	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 5,433 bp · p 3.8e-05 · regional, not allelic
Overall
CADD	32.0	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

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000929% 15/1,613,994 alleles · very rare exomes 13/1,461,824 · genomes 2/152,170 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00781%	12,801
East Asiangrpmax	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,092
European (non-Finnish)	0.000593%	168,573

Finnish 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.Arg409Trp
Coding: c.1225C>T
MANE Select: NM_016938
dbSNP: rs774325189
Type: single nucleotide variant
Location: chr11:65867025 (GRCh38)

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

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-arg409trp (accessed [today's date]).

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