Is EFEMP2 p.Ser266Pro (c.796T>C) pathogenic?

EFEMP2 p.Ser266Pro (c.796T>C) is classified Likely benign in EFEMP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-23). AlphaMissense: likely pathogenic (0.9859); Very rare (popmax 0.00266%, afr); Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.Ser266Pro (c.796T>C)?

EFEMP2 p.Ser266Pro (c.796T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is EFEMP2 p.Ser266Pro (c.796T>C) in the general population?

EFEMP2 p.Ser266Pro (c.796T>C) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about EFEMP2 p.Ser266Pro (c.796T>C)?

AlphaMissense predicts likely pathogenic (score 0.9859) — an in-silico prediction, not a clinical call.

EFEMP2 p.Ser266Pro

c.796T>C · VCV3506982

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9859 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9859	likely pathogenic
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -12.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	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	28.0	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 0.00266% African / African-American · 2/75,050 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.0108% 158/1,461,188 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.205%	488
Remaining individualsnot grpmax-eligible	0.024%	4,163
African / African-Americangrpmax	0.00266%	37,525
Admixed American	0.00167%	60,018
European (non-Finnish)	0.000847%	117,996

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.Ser266Pro
Coding: c.796T>C
MANE Select: NM_016938
Type: single nucleotide variant
Location: chr11:65868561 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB
Residue 266: a disulfide bond; the egf-like 5; calcium-binding 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

Similar variants

EFEMP2 p.Glu167Ter Pathogenic ★★ same condition
EFEMP2 c.608-3C>G Uncertain significance ★★ same condition
EFEMP2 p.Ala103Thr Uncertain significance ★★ ⚠ same condition
EFEMP2 p.Ala291Gly Uncertain significance ★★ ⚠ same condition
EFEMP2 p.Ala85Thr Uncertain significance ★★ ⚠ same condition
EFEMP2 p.Ala86Thr Uncertain significance ★★ ⚠ same condition
EFEMP2 p.Arg156Cys Uncertain significance ★★ ⚠ same condition
EFEMP2 p.Arg169Cys 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-ser266pro (accessed [today's date]).

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