Is ERCC8 p.Pro383Leu (c.1148C>T) pathogenic?

ERCC8 p.Pro383Leu (c.1148C>T) is classified Uncertain significance in ERCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). AlphaMissense: likely benign (0.1003); Ultra-rare (popmax 0.0166%, mid).

How common is ERCC8 p.Pro383Leu (c.1148C>T) in the general population?

ERCC8 p.Pro383Leu (c.1148C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about ERCC8 p.Pro383Leu (c.1148C>T)?

AlphaMissense predicts likely benign (score 0.1003) — an in-silico prediction, not a clinical call.

ERCC8 p.Pro383Leu

c.1148C>T · rs754566666 · VCV1398886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1003 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1003	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -7.81	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 1.5	GERP -0.76, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 70 kb · p 0.027 · regional, not allelic
Overall
CADD	20.8	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 0.0166% Middle Eastern · 1/6,014 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00155% 25/1,610,660 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,014
East Asian	0.00446%	22,410
South Asian	0.00223%	44,895
European (non-Finnish)	0.00161%	62,061
African / African-American	0.00134%	74,632

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.Pro383Leu
Coding: c.1148C>T
MANE Select: NM_000082
dbSNP: rs754566666
Type: single nucleotide variant
Location: chr5:60874658 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 383: a UniProt-annotated variant site (in csa); an α-helix; the 'disordered' region

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

Similar variants

ERCC8 p.Pro383= Likely benign ★ same residue
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

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-pro383leu (accessed [today's date]).

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