Is EFEMP1 p.Arg440Gln (c.1319G>A) pathogenic?

EFEMP1 p.Arg440Gln (c.1319G>A) is classified Uncertain significance in EFEMP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-20). AlphaMissense: ambiguous (0.3558); Ultra-rare (popmax 0.0187%, afr).

How common is EFEMP1 p.Arg440Gln (c.1319G>A) in the general population?

EFEMP1 p.Arg440Gln (c.1319G>A) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about EFEMP1 p.Arg440Gln (c.1319G>A)?

AlphaMissense predicts ambiguous (score 0.3558) — an in-silico prediction, not a clinical call.

EFEMP1 p.Arg440Gln

c.1319G>A · rs373990093 · VCV1525751

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3558 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3558	ambiguous
REVEL	0.77	pathogenic-leaning
SaProt	LLR -7.29	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 51 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	34.0	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 0.0187% African / African-American · 14/74,884 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00149% 24/1,613,366 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,349
East Asian	0.00891%	11,220
Admixed American	0.00334%	29,969
Remaining individualsnot grpmax-eligible	0.0016%	62,466
European (non-Finnish)	0.000254%	393,210

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.Arg440Gln
Coding: c.1319G>A
MANE Select: NM_001039348
dbSNP: rs373990093
Type: single nucleotide variant
Location: chr2:55870721 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 440: a UniProt-annotated variant site (in arcl1d; likely pathogenic); the 'mediates interaction with timp3' region

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

Similar variants

EFEMP1 p.Arg440Ter Uncertain significance ★ 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
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-arg440gln (accessed [today's date]).

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