Is ERCC3 p.Lys117Asn (c.351A>T) pathogenic?

ERCC3 p.Lys117Asn (c.351A>T) is classified Uncertain significance in ERCC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-08). AlphaMissense: likely pathogenic (0.9339); Very rare (popmax 0.00398%, nfe).

How common is ERCC3 p.Lys117Asn (c.351A>T) in the general population?

ERCC3 p.Lys117Asn (c.351A>T) is very rare (popmax 0.00398%, nfe) (gnomAD).

What do computational predictors say about ERCC3 p.Lys117Asn (c.351A>T)?

AlphaMissense predicts likely pathogenic (score 0.9339) — an in-silico prediction, not a clinical call.

ERCC3 p.Lys117Asn

c.351A>T · rs762430357 · VCV1696085

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9339 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9339	likely pathogenic
REVEL	0.25	benign-leaning
SaProt	LLR -13.47	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.34	GERP -4.7, phastCons 0.27
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	16.5	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 0.00398% European (non-Finnish) · 47/1,180,032 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00304% 49/1,613,976 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00398%	25,107
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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: ERCC3
Protein: p.Lys117Asn
Coding: c.351A>T
MANE Select: NM_000122
dbSNP: rs762430357
Type: single nucleotide variant
Location: chr2:127292730 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 117: a UniProt-annotated variant site (in); a β-strand

Full ERCC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERCC3 p.Lys117Arg Uncertain significance ★★ ⚠ same residue
ERCC3 c.1828-1G>C Likely pathogenic ★★ same type
ERCC3 c.471+1G>A Pathogenic ★★ same type
ERCC3 c.657+1G>A Likely pathogenic ★★ same type
ERCC3 p.Arg109Ter Pathogenic/Likely pathogenic ★★ same type
ERCC3 p.Arg195Ter Pathogenic ★★ same type
ERCC3 p.Arg234Ter Pathogenic/Likely pathogenic ★★ same type
ERCC3 p.Arg425Ter 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/ercc3-p-lys117asn (accessed [today's date]).

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