Is ERCC8 p.Phe4Leu (c.10T>C) pathogenic?

ERCC8 p.Phe4Leu (c.10T>C) is classified Uncertain significance in ERCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-03). AlphaMissense: likely pathogenic (0.7536); Ultra-rare (popmax 0.01%, amr).

How common is ERCC8 p.Phe4Leu (c.10T>C) in the general population?

ERCC8 p.Phe4Leu (c.10T>C) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ERCC8 p.Phe4Leu (c.10T>C)?

AlphaMissense predicts likely pathogenic (score 0.7536) — an in-silico prediction, not a clinical call.

ERCC8 p.Phe4Leu

c.10T>C · rs764406810 · VCV2069165

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7536 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7536	likely pathogenic
REVEL	0.092	moderately benign-leaning
SaProt	LLR -5.00	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP -0.67, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 70 kb · p 0.027 · regional, not allelic
Overall
CADD	17.36	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 0.01% Admixed American · 6/59,956 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000372% 6/1,613,438 alleles · ultra-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: ERCC8
Protein: p.Phe4Leu
Coding: c.10T>C
MANE Select: NM_000082
dbSNP: rs764406810
Type: single nucleotide variant
Location: chr5:60944999 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 4: an α-helix

Full ERCC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERCC8 c.1041+1G>T Pathogenic/Likely pathogenic ★★ same type
ERCC8 c.1042-2A>G Pathogenic/Likely pathogenic ★★ same type
ERCC8 c.173+1119G>C Pathogenic/Likely pathogenic ★★ same type
ERCC8 c.173+1G>A Pathogenic/Likely pathogenic ★★ same type
ERCC8 c.275+1G>A Pathogenic ★★ same type
ERCC8 c.276-1G>A Likely pathogenic ★★ same type
ERCC8 c.399+1G>A Likely pathogenic ★★ same type
ERCC8 c.551-1G>A Pathogenic ★★ same type

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/ercc8-p-phe4leu (accessed [today's date]).

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