Is EFEMP2 p.His92= (c.276C>T) pathogenic?

EFEMP2 p.His92= (c.276C>T) is classified Benign in EFEMP2 (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-04). Common (popmax 58.5%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.His92= (c.276C>T)?

EFEMP2 p.His92= (c.276C>T) is associated with Cardiovascular phenotype, cutis laxa, autosomal recessive, type 1B, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

EFEMP2 p.His92=

Q: How common is EFEMP2 p.His92= (c.276C>T) in the general population?

EFEMP2 p.His92= (c.276C>T) is common (popmax 58.5%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.276C>T · rs633800 · VCV163326

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

gnomAD v4.1

Common

common (popmax 58.5%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.99	GERP -3.2
Overall
CADD	2.702	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 58.5% Middle Eastern · 3,545/6,062 alleles

Filtering AF 56.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.2%

Overall 48.1% 776,844/1,613,952 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	58.5%	2
Finnishnot grpmax-eligible	56.7%	2
South Asian	56.4%	2
European (non-Finnish)	51%	2
Ashkenazi Jewishnot grpmax-eligible	49.5%	2
Remaining individualsnot grpmax-eligible	46.9%	2
Amishnot grpmax-eligible	41.9%	2
Admixed American	30.8%	3
East Asian	19.9%	5
African / African-American	15.7%	6

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.His92=
Coding: c.276C>T
MANE Select: NM_016938
dbSNP: rs633800
Type: single nucleotide variant
Location: chr11:65871248 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB
Residue 92: a functional site (cleavage); a disulfide bond

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.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
EFEMP2 c.491-5C>G Uncertain significance ★★ same condition
EFEMP2 c.608-3C>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-his92 (accessed [today's date]).

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