Is ERCC2 p.Lys751Gln (c.2251A>C) pathogenic?

ERCC2 p.Lys751Gln (c.2251A>C) is classified Benign/Likely benign in ERCC2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0566); Common (popmax 39.6%, mid) — too common for a highly-penetrant pathogenic allele; Associated with trichothiodystrophy 1, photosensitive.

What condition is associated with ERCC2 p.Lys751Gln (c.2251A>C)?

ERCC2 p.Lys751Gln (c.2251A>C) is associated with trichothiodystrophy 1, photosensitive, xeroderma pigmentosum group D, cerebrooculofacioskeletal syndrome 2 (ClinVar).

What do computational predictors say about ERCC2 p.Lys751Gln (c.2251A>C)?

AlphaMissense predicts likely benign (score 0.0566) — an in-silico prediction, not a clinical call.

ERCC2 p.Lys751Gln

Q: How common is ERCC2 p.Lys751Gln (c.2251A>C) in the general population?

ERCC2 p.Lys751Gln (c.2251A>C) is common (popmax 39.6%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2251A>C · rs13181 · VCV134105

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0566 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 39.6%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trichothiodystrophy 1, photosensitive

Computational evidence

Protein change
AlphaMissense	0.0566	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -5.11	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 6.4	GERP -1.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	12.63	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 39.6% Middle Eastern · 2,399/6,062 alleles

Filtering AF 38.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 37.7%

Overall 35.1% 567,102/1,613,486 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	42.1%	2
Finnishnot grpmax-eligible	41.7%	2
Ashkenazi Jewishnot grpmax-eligible	41.3%	2
Middle Easterngrpmax	39.6%	3
South Asian	37.6%	3
European (non-Finnish)	37.1%	3
Remaining individualsnot grpmax-eligible	34.2%	3
African / African-American	22.8%	4
Admixed American	21.8%	5
East Asian	5.76%	17

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Osteosarcoma	Cisplatin	B	Resistance
Lung Non-small Cell Carcinoma	Paclitaxel,Carboplatin	B	Sensitivity/Response

Variant & gene context

Gene: ERCC2
Protein: p.Lys751Gln
Coding: c.2251A>C
MANE Select: NM_000400
dbSNP: rs13181
Type: single nucleotide variant
Location: chr19:45351661 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 751: a UniProt-annotated variant site (in)

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

trichothiodystrophy 1, photosensitive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group D cerebrooculofacioskeletal syndrome 2

Similar variants

ERCC2 p.Lys751Arg Uncertain significance ★ ⚠ same residue
ERCC2 p.Lys751= Likely benign ★★ same residue
ERCC2 p.Lys751Ter Uncertain significance ★ same residue
ERCC2 c.1238-1G>C Likely pathogenic ★★ same condition
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1378-1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1479+2T>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1480-1G>C Pathogenic/Likely pathogenic ★★ 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/ercc2-p-lys751gln (accessed [today's date]).

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