Is EFEMP2 p.Leu21= (c.63C>T) pathogenic?

EFEMP2 p.Leu21= (c.63C>T) is classified Conflicting classifications of pathogenicity in EFEMP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-31). Very rare (popmax 0.00238%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EFEMP2 p.Leu21= (c.63C>T)?

EFEMP2 p.Leu21= (c.63C>T) is associated with Cardiovascular phenotype, cutis laxa, autosomal recessive, type 1B (ClinVar).

How common is EFEMP2 p.Leu21= (c.63C>T) in the general population?

EFEMP2 p.Leu21= (c.63C>T) is very rare (popmax 0.00238%, sas) (gnomAD).

EFEMP2 p.Leu21=

c.63C>T · rs1442174846 · VCV877754

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00238%, sas)

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 2.1	GERP 0.84, phastCons 1
Overall
CADD	5.124	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00238% South Asian · 2/84,062 alleles

Filtering AF 0.000395% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000148%

Overall 0.000322% 5/1,551,622 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00238%	42,031
African / African-American	0.00137%	73,058
European (non-Finnish)	0.000174%	573,519

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.Leu21=
Coding: c.63C>T
MANE Select: NM_016938
dbSNP: rs1442174846
Type: single nucleotide variant
Location: chr11:65872292 (GRCh38)
Gene constraint: LOEUF 0.56 · pLI 0.62 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 1 PDB

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-leu21 (accessed [today's date]).

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