Is EFEMP1 p.Ser492Leu (c.1475C>T) pathogenic?

EFEMP1 p.Ser492Leu (c.1475C>T) is classified Uncertain significance in EFEMP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-09). AlphaMissense: likely benign (0.177); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with EFEMP1 p.Ser492Leu (c.1475C>T)?

EFEMP1 p.Ser492Leu (c.1475C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EFEMP1 p.Ser492Leu (c.1475C>T) in the general population?

EFEMP1 p.Ser492Leu (c.1475C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about EFEMP1 p.Ser492Leu (c.1475C>T)?

AlphaMissense predicts likely benign (score 0.177) — an in-silico prediction, not a clinical call.

EFEMP1 p.Ser492Leu

c.1475C>T · VCV3506960

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.177 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.177	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -4.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 51 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	25.2	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 0.00223% East Asian · 1/44,876 alleles

Overall 6.85e-05% 1/1,460,382 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.Ser492Leu
Coding: c.1475C>T
MANE Select: NM_001039348
Type: single nucleotide variant
Location: chr2:55867080 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.67
Residue 492: 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

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-ser492leu (accessed [today's date]).

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