Is ERCC4 p.Leu185Ile (c.553C>A) pathogenic?

ERCC4 p.Leu185Ile (c.553C>A) is classified Uncertain significance in ERCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-17). AlphaMissense: likely benign (0.3243); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with ERCC4 p.Leu185Ile (c.553C>A)?

ERCC4 p.Leu185Ile (c.553C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC4 p.Leu185Ile (c.553C>A) in the general population?

ERCC4 p.Leu185Ile (c.553C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ERCC4 p.Leu185Ile (c.553C>A)?

AlphaMissense predicts likely benign (score 0.3243) — an in-silico prediction, not a clinical call.

ERCC4 p.Leu185Ile

c.553C>A · rs767437700 · VCV2526533

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3243	likely benign
REVEL	0.496	indeterminate
SaProt	LLR -11.04	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	24.2	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 0.0011% South Asian · 1/91,068 alleles

Overall 6.84e-05% 1/1,461,668 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: ERCC4
Protein: p.Leu185Ile
Coding: c.553C>A
MANE Select: NM_005236
dbSNP: rs767437700
Type: single nucleotide variant
Location: chr16:13926725 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 13 PDB
Residue 185: the 'helicase-like' region

Full ERCC4 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

ERCC4 p.Leu185= Likely benign ★ same residue
ERCC4 p.Ala874Thr Uncertain significance ★★ ⚠ same condition
ERCC4 p.Arg158His Uncertain significance ★★ ⚠ same condition
ERCC4 p.Arg598Lys Uncertain significance ★★ ⚠ same condition
ERCC4 p.Arg618His Uncertain significance ★★ ⚠ same condition
ERCC4 p.Arg864Cys Uncertain significance ★★ ⚠ same condition
ERCC4 p.Arg9Gly Uncertain significance ★★ ⚠ same condition
ERCC4 p.Asp664Tyr 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/ercc4-p-leu185ile (accessed [today's date]).

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