Is EFEMP1 p.Ala126Pro (c.376G>C) pathogenic?

EFEMP1 p.Ala126Pro (c.376G>C) is classified Uncertain significance in EFEMP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-22). AlphaMissense: likely benign (0.1018); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with EFEMP1 p.Ala126Pro (c.376G>C)?

EFEMP1 p.Ala126Pro (c.376G>C) is associated with Inborn genetic diseases (ClinVar).

How common is EFEMP1 p.Ala126Pro (c.376G>C) in the general population?

EFEMP1 p.Ala126Pro (c.376G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EFEMP1 p.Ala126Pro (c.376G>C)?

AlphaMissense predicts likely benign (score 0.1018) — an in-silico prediction, not a clinical call.

EFEMP1 p.Ala126Pro

c.376G>C · rs373554215 · VCV1058543

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1018 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1018	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 51 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	19.84	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EFEMP1
Protein: p.Ala126Pro
Coding: c.376G>C
MANE Select: NM_001039348
dbSNP: rs373554215
Type: single nucleotide variant
Location: chr2:55917806 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EFEMP1 p.Ala126Thr Uncertain significance ★★ ⚠ same residue
EFEMP1 p.Ala447Thr Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Arg208Gln Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Arg362Gln Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Arg401Gln Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Asn80Ser Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Gln200His Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Gly100Arg 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/efemp1-p-ala126pro (accessed [today's date]).

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