Is ERCC2 p.Ala34Thr (c.100G>A) pathogenic?

ERCC2 p.Ala34Thr (c.100G>A) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-11-20). AlphaMissense: ambiguous (0.5471); Ultra-rare (popmax 0.0661%, mid); Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 p.Ala34Thr (c.100G>A)?

ERCC2 p.Ala34Thr (c.100G>A) is associated with xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive, cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Ala34Thr (c.100G>A) in the general population?

ERCC2 p.Ala34Thr (c.100G>A) is ultra-rare (popmax 0.0661%, mid) (gnomAD).

What do computational predictors say about ERCC2 p.Ala34Thr (c.100G>A)?

AlphaMissense predicts ambiguous (score 0.5471) — an in-silico prediction, not a clinical call.

ERCC2 p.Ala34Thr

Q: How is Xeroderma pigmentosum-Cockayne syndrome complex inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.100G>A · rs768632615 · VCV1394100

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5471 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

xeroderma pigmentosum group D

Computational evidence

Protein change
AlphaMissense	0.5471	ambiguous
REVEL	0.269	benign-leaning
SaProt	LLR -9.28	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.6, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 406 bp · p 0.14 · regional, not allelic
Overall
CADD	27.4	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 0.0661% Middle Eastern · 4/6,054 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.000558% 9/1,612,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,514
Remaining individualsnot grpmax-eligible	0.0032%	31,211
European (non-Finnish)	0.000254%	393,059

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: ERCC2
Protein: p.Ala34Thr
Coding: c.100G>A
MANE Select: NM_000400
dbSNP: rs768632615
Type: single nucleotide variant
Location: chr19:45370138 (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 34: the helicase atp-binding domain; an α-helix

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

Disease context

xeroderma pigmentosum group D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: trichothiodystrophy 1, photosensitive cerebrooculofacioskeletal syndrome 2

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC2 p.Ala34= Likely benign ★★ same residue
ERCC2 p.Ala34Pro 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
ERCC2 c.1480-2A>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-ala34thr (accessed [today's date]).

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