Is EFEMP1 p.Ala4= (c.12C>T) pathogenic?

EFEMP1 p.Ala4= (c.12C>T) is classified Likely benign in EFEMP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-18). Ultra-rare (popmax 0.0117%, amr).

How common is EFEMP1 p.Ala4= (c.12C>T) in the general population?

EFEMP1 p.Ala4= (c.12C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

EFEMP1 p.Ala4=

c.12C>T · rs539120761 · VCV1591647

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

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 0.75	GERP -3.2, phastCons 0.9
Overall
CADD	12.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,996 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000496% 8/1,613,736 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,571
Remaining individualsnot grpmax-eligible	0.0016%	62,494

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: EFEMP1
Protein: p.Ala4=
Coding: c.12C>T
MANE Select: NM_001039348
dbSNP: rs539120761
Type: single nucleotide variant
Location: chr2:55922429 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67

Full EFEMP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFEMP1 p.Ala4Asp Uncertain significance ★ ⚠ same residue
EFEMP1 p.Ala4Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
EFEMP1 p.Arg345Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
EFEMP1 p.Ala104Thr Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala126Pro Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala126Thr Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala447Ser Uncertain significance ★★ ⚠ same type
EFEMP1 p.Ala447Thr Uncertain significance ★★ ⚠ same type

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/efemp1-p-ala4 (accessed [today's date]).

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