Is EFEMP1 p.Arg345Gln (c.1034G>A) pathogenic?

EFEMP1 p.Arg345Gln (c.1034G>A) is classified Uncertain significance in EFEMP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-09). AlphaMissense: likely benign (0.1054); Very rare (popmax 0.00267%, afr).

How common is EFEMP1 p.Arg345Gln (c.1034G>A) in the general population?

EFEMP1 p.Arg345Gln (c.1034G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about EFEMP1 p.Arg345Gln (c.1034G>A)?

AlphaMissense predicts likely benign (score 0.1054) — an in-silico prediction, not a clinical call.

EFEMP1 p.Arg345Gln

c.1034G>A · VCV4697663

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1054	likely benign
REVEL	0.384	indeterminate
SaProt	LLR -8.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 51 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	21.1	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

Grpmax group 0.00267% African / African-American · 2/74,878 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000434% 7/1,613,522 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,439
South Asian	0.0011%	91,080
European (non-Finnish)	0.000339%	294,932

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.Arg345Gln
Coding: c.1034G>A
MANE Select: NM_001039348
Type: single nucleotide variant
Location: chr2:55871090 (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

Similar variants

EFEMP1 p.Arg345Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
EFEMP1 p.Arg345= Likely benign ★ same residue
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
EFEMP1 p.Arg148His 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-arg345gln (accessed [today's date]).

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