Is EFEMP1 p.Arg358Cys (c.1072C>T) pathogenic?

EFEMP1 p.Arg358Cys (c.1072C>T) is classified Uncertain significance in EFEMP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-09). AlphaMissense: likely pathogenic (0.9052); Very rare (popmax 0.00102%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EFEMP1 p.Arg358Cys (c.1072C>T)?

EFEMP1 p.Arg358Cys (c.1072C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EFEMP1 p.Arg358Cys (c.1072C>T) in the general population?

EFEMP1 p.Arg358Cys (c.1072C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about EFEMP1 p.Arg358Cys (c.1072C>T)?

AlphaMissense predicts likely pathogenic (score 0.9052) — an in-silico prediction, not a clinical call.

EFEMP1 p.Arg358Cys

c.1072C>T · rs765589888 · VCV2259874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9052	likely pathogenic
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -12.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, 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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00102% European (non-Finnish) · 12/1,179,800 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000744% 12/1,613,562 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.Arg358Cys
Coding: c.1072C>T
MANE Select: NM_001039348
dbSNP: rs765589888
Type: single nucleotide variant
Location: chr2:55871052 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 358: a disulfide bond; a UniProt-annotated variant site (in arcl1d; likely pathogenic); 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

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

Similar variants

EFEMP1 p.Arg358His Uncertain significance ★ same residue
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

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-arg358cys (accessed [today's date]).

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