Is ERCC8 p.Ser314Arg (c.940A>C) pathogenic?

ERCC8 p.Ser314Arg (c.940A>C) is classified Uncertain significance in ERCC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-03). AlphaMissense: likely pathogenic (0.684); Very rare (popmax 0.00271%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERCC8 p.Ser314Arg (c.940A>C)?

ERCC8 p.Ser314Arg (c.940A>C) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC8 p.Ser314Arg (c.940A>C) in the general population?

ERCC8 p.Ser314Arg (c.940A>C) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about ERCC8 p.Ser314Arg (c.940A>C)?

AlphaMissense predicts likely pathogenic (score 0.684) — an in-silico prediction, not a clinical call.

ERCC8 p.Ser314Arg

c.940A>C · rs373203544 · VCV1693896

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.684 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.684	likely pathogenic
REVEL	0.648	pathogenic-leaning
SaProt	LLR -8.43	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.38, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 70 kb · p 0.027 · regional, not allelic
Overall
CADD	22.9	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 0.00271% European (non-Finnish) · 32/1,179,078 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00198% 32/1,612,788 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.Ser314Arg
Coding: c.940A>C
MANE Select: NM_000082
dbSNP: rs373203544
Type: single nucleotide variant
Location: chr5:60890990 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 16 PDB

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.Ser314= Likely benign ★★ same residue
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

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-ser314arg (accessed [today's date]).

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