Is ERCC5 p.Ala376Val (c.1127C>T) pathogenic?

ERCC5 p.Ala376Val (c.1127C>T) is classified Likely benign in ERCC5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.0927); Rare (popmax 0.239%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with ERCC5 p.Ala376Val (c.1127C>T)?

ERCC5 p.Ala376Val (c.1127C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is ERCC5 p.Ala376Val (c.1127C>T) in the general population?

ERCC5 p.Ala376Val (c.1127C>T) is rare (popmax 0.239%, afr) (gnomAD).

What do computational predictors say about ERCC5 p.Ala376Val (c.1127C>T)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

ERCC5 p.Ala376Val

c.1127C>T · rs56398372 · VCV134187

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.239%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -6.35	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 0.91	GERP -0.45
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.087 · regional, not allelic
Overall
CADD	7.129	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 0.239% African / African-American · 179/75,034 alleles

Filtering AF 0.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.199%

Overall 0.0132% 213/1,614,166 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.239%	419
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0256%	3,907
Admixed American	0.02%	5,002
South Asian	0.0022%	45,543
European (non-Finnish)	0.000169%	590,030

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: ERCC5
Protein: p.Ala376Val
Coding: c.1127C>T
MANE Select: NM_000123
dbSNP: rs56398372
Type: single nucleotide variant
Location: chr13:102862276 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.91 · 10 PDB
Residue 376: the 'spacer region' region; the 'disordered' region

Full ERCC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERCC5 p.Glu1090Lys Uncertain significance ★★ ⚠ same condition
ERCC5 p.Glu595Gln Uncertain significance ★★ ⚠ same condition
ERCC5 p.Asp379= Likely benign ★★ same condition
ERCC5 p.Glu267= Benign/Likely benign ★★ same condition
ERCC5 p.Ala1007Gly Uncertain significance ★ ⚠ same condition
ERCC5 p.Arg1166= Uncertain significance ★ same condition
ERCC5 p.Arg366Gln Uncertain significance ★ ⚠ same condition
ERCC5 p.Glu302Ala 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/ercc5-p-ala376val (accessed [today's date]).

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