Is EFEMP2 p.Tyr252= (c.756C>T) pathogenic?

EFEMP2 p.Tyr252= (c.756C>T) is classified Likely benign in EFEMP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-18). Ultra-rare (popmax 0.033%, mid); Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.Tyr252= (c.756C>T)?

EFEMP2 p.Tyr252= (c.756C>T) is associated with Cardiovascular phenotype, cutis laxa, autosomal recessive, type 1B (ClinVar).

How common is EFEMP2 p.Tyr252= (c.756C>T) in the general population?

EFEMP2 p.Tyr252= (c.756C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

EFEMP2 p.Tyr252=

c.756C>T · rs1391116927 · VCV682444

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

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 0.87	GERP -3.1, phastCons 0.99
Overall
CADD	6.169	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000372% 6/1,613,946 alleles · ultra-rare exomes 6/1,461,612 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0016%	62,506
South Asian	0.0011%	91,088
European (non-Finnish)	0.000169%	590,016

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.Tyr252=
Coding: c.756C>T
MANE Select: NM_016938
dbSNP: rs1391116927
Type: single nucleotide variant
Location: chr11:65868601 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB
Residue 252: 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

Also linked: cutis laxa, autosomal recessive, type 1B

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-tyr252 (accessed [today's date]).

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