Is EFEMP1 p.Arg345Trp (c.1033C>T) pathogenic?

EFEMP1 p.Arg345Trp (c.1033C>T) is classified Pathogenic/Likely pathogenic in EFEMP1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-04-13). AlphaMissense: ambiguous (0.3567); Very rare (popmax 0.00153%, nfe); Associated with EFEMP1-related disorders.

What condition is associated with EFEMP1 p.Arg345Trp (c.1033C>T)?

EFEMP1 p.Arg345Trp (c.1033C>T) is associated with EFEMP1-related disorders, retinal disorder, Doyne honeycomb retinal dystrophy (ClinVar).

How common is EFEMP1 p.Arg345Trp (c.1033C>T) in the general population?

EFEMP1 p.Arg345Trp (c.1033C>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about EFEMP1 p.Arg345Trp (c.1033C>T)?

AlphaMissense predicts ambiguous (score 0.3567) — an in-silico prediction, not a clinical call.

EFEMP1 p.Arg345Trp

c.1033C>T · rs121434491 · VCV8072

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.3567 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

EFEMP1-related disorders

Computational evidence

Protein change
AlphaMissense	0.3567	ambiguous
REVEL	0.709	pathogenic-leaning
SaProt	LLR -12.63	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.27	acceptor loss · deltas
Pangolin	Δ0.29	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 51 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	25.5	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

Grpmax group 0.00153% European (non-Finnish) · 18/1,179,708 alleles

Filtering AF 0.000954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00123% 18/1,461,422 alleles · very rare

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.Arg345Trp
Coding: c.1033C>T
MANE Select: NM_001039348
dbSNP: rs121434491
Type: single nucleotide variant
Location: chr2:55871091 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 345: a disulfide bond; a UniProt-annotated variant site (in arcl1d; likely pathogenic); a UniProt-annotated variant site (in dhrd; misfolded, accumulates in cells due to inefficient secretion; induces the formation of deposits between bruch's membrane and the retinal pigment epithelium where it accumulates); the egf-like 6; calcium-binding domain; the 'mediates interaction with timp3' region

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

Disease context

EFEMP1-related disorders

Also linked: retinal disorder Doyne honeycomb retinal dystrophy inherited retinal dystrophy

Similar variants

EFEMP1 p.Arg345Gln Uncertain significance ★★ ⚠ same residue
EFEMP1 p.Arg345= Likely benign ★ same residue
EFEMP1 p.Ala447Ser Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Glu374Gln Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Met130Thr Uncertain significance ★★ ⚠ same condition
EFEMP1 p.Pro373Leu Uncertain significance ★★ ⚠ same condition
EFEMP1 c.1001-14C>T Benign ★★ same condition
EFEMP1 c.518-11G>A Benign ★★ 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-arg345trp (accessed [today's date]).

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