Is ERCC8 p.Lys331Glu (c.991A>G) pathogenic?

ERCC8 p.Lys331Glu (c.991A>G) is classified Uncertain significance in ERCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: likely benign (0.2709); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ERCC8 p.Lys331Glu (c.991A>G)?

ERCC8 p.Lys331Glu (c.991A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC8 p.Lys331Glu (c.991A>G) in the general population?

ERCC8 p.Lys331Glu (c.991A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ERCC8 p.Lys331Glu (c.991A>G)?

AlphaMissense predicts likely benign (score 0.2709) — an in-silico prediction, not a clinical call.

ERCC8 p.Lys331Glu

c.991A>G · rs989442602 · VCV2494379

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2709	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -7.75	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 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 70 kb · p 0.027 · regional, not allelic
Overall
CADD	22.7	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 0.00133% African / African-American · 1/74,928 alleles

Overall 0.000657% 1/152,210 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: ERCC8
Protein: p.Lys331Glu
Coding: c.991A>G
MANE Select: NM_000082
dbSNP: rs989442602
Type: single nucleotide variant
Location: chr5:60890939 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB
Residue 331: a UniProt-annotated variant site (in csa)

Full ERCC8 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

ERCC8 p.Arg270Ser Uncertain significance ★★ ⚠ same condition
ERCC8 p.Asp136Gly Uncertain significance ★★ ⚠ same condition
ERCC8 p.Asp373Tyr Uncertain significance ★★ ⚠ same condition
ERCC8 p.Asp72His Uncertain significance ★★ ⚠ same condition
ERCC8 p.Gln169His Uncertain significance ★★ ⚠ same condition
ERCC8 p.Glu325Lys Uncertain significance ★★ ⚠ same condition
ERCC8 p.Gly91Arg Uncertain significance ★★ ⚠ same condition
ERCC8 p.Ile189Val 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/ercc8-p-lys331glu (accessed [today's date]).

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