Is ERCC1 p.Arg156Trp (c.466C>T) pathogenic?

ERCC1 p.Arg156Trp (c.466C>T) is classified Conflicting classifications of pathogenicity in ERCC1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-19). AlphaMissense: likely pathogenic (0.9557); Ultra-rare (popmax 0.0165%, nfe); Associated with Cholestatic liver disease.

What condition is associated with ERCC1 p.Arg156Trp (c.466C>T)?

ERCC1 p.Arg156Trp (c.466C>T) is associated with Cholestatic liver disease, premature menopause, skin sensitivity to sun (ClinVar).

How common is ERCC1 p.Arg156Trp (c.466C>T) in the general population?

ERCC1 p.Arg156Trp (c.466C>T) is ultra-rare (popmax 0.0165%, nfe) (gnomAD).

What do computational predictors say about ERCC1 p.Arg156Trp (c.466C>T)?

AlphaMissense predicts likely pathogenic (score 0.9557) — an in-silico prediction, not a clinical call.

ERCC1 p.Arg156Trp

c.466C>T · rs757369063 · VCV978472

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9557 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cholestatic liver disease

Computational evidence

Protein change
AlphaMissense	0.9557	likely pathogenic
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -15.89	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 1.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.16 · regional, not allelic
Overall
CADD	31.0	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 0.0165% European (non-Finnish) · 193/1,171,632 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0128% 204/1,598,228 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0165%	6,071
Admixed American	0.0103%	9,677
Remaining individualsnot grpmax-eligible	0.00646%	15,471
East Asian	0.00225%	44,530

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: ERCC1
Protein: p.Arg156Trp
Coding: c.466C>T
MANE Select: NM_001983
dbSNP: rs757369063
Type: single nucleotide variant
Location: chr19:45419157 (GRCh38)
Gene constraint: LOEUF 1.306 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 14 PDB
Residue 156: a DNA-binding region; an α-helix

Full ERCC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cholestatic liver disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: premature menopause skin sensitivity to sun cerebrooculofacioskeletal syndrome 4

Similar variants

ERCC1 p.Arg156Gln Uncertain significance ★★ ⚠ same residue
ERCC1 p.Arg41Ter Pathogenic ★★ same condition
ERCC1 p.Asn110Ser Uncertain significance ★★ ⚠ same condition
ERCC1 p.Ser267Pro Uncertain significance ★★ ⚠ same condition
ERCC1 c.843+32G>A Benign/Likely benign ★★ same condition
POLR1G p.Thr282Ala Benign ★★ same condition
ERCC1 p.Glu62Ter Likely pathogenic ★ same condition
ERCC1 p.Phe231Leu Pathogenic ★ ⚠ 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/ercc1-p-arg156trp (accessed [today's date]).

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