Is EFEMP1 p.Asp46Ala (c.137A>C) pathogenic?

EFEMP1 p.Asp46Ala (c.137A>C) is classified Uncertain significance in EFEMP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-31). AlphaMissense: likely pathogenic (0.9794); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with EFEMP1 p.Asp46Ala (c.137A>C)?

EFEMP1 p.Asp46Ala (c.137A>C) is associated with Inborn genetic diseases (ClinVar).

How common is EFEMP1 p.Asp46Ala (c.137A>C) in the general population?

EFEMP1 p.Asp46Ala (c.137A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EFEMP1 p.Asp46Ala (c.137A>C)?

AlphaMissense predicts likely pathogenic (score 0.9794) — an in-silico prediction, not a clinical call.

EFEMP1 p.Asp46Ala

c.137A>C · VCV4838904

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9794 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9794	likely pathogenic
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -9.33	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 4,438 bp · p 0.41 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

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.Asp46Ala
Coding: c.137A>C
MANE Select: NM_001039348
Type: single nucleotide variant
Location: chr2:55918045 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 46: the egf-like 1; atypical domain

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.Ala126Pro Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Ala126Thr Uncertain significance ★★ ⚠ same condition
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

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-asp46ala (accessed [today's date]).

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