Is ERCC2 p.Val536Met (c.1606G>A) pathogenic?

ERCC2 p.Val536Met (c.1606G>A) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-03-09). AlphaMissense: likely pathogenic (0.972); Ultra-rare (popmax 0.053%, nfe); Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 p.Val536Met (c.1606G>A)?

ERCC2 p.Val536Met (c.1606G>A) is associated with xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive, cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Val536Met (c.1606G>A) in the general population?

ERCC2 p.Val536Met (c.1606G>A) is ultra-rare (popmax 0.053%, nfe) (gnomAD).

What do computational predictors say about ERCC2 p.Val536Met (c.1606G>A)?

AlphaMissense predicts likely pathogenic (score 0.972) — an in-silico prediction, not a clinical call.

ERCC2 p.Val536Met

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

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

c.1606G>A · rs142568756 · VCV893766

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.972 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.053%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group D

Computational evidence

Protein change
AlphaMissense	0.972	likely pathogenic
REVEL	0.718	pathogenic-leaning
SaProt	LLR -13.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.053% European (non-Finnish) · 625/1,179,948 alleles

Filtering AF 0.0495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0482%

Overall 0.0428% 690/1,613,940 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.053%	1,888
Remaining individualsnot grpmax-eligible	0.0368%	2,717
Admixed American	0.025%	4,001
Finnishnot grpmax-eligible	0.0219%	4,573
African / African-American	0.0133%	7,491
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
East Asian	0.00223%	44,898
South Asian	0.0011%	91,072

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.Val536Met
Coding: c.1606G>A
MANE Select: NM_000400
dbSNP: rs142568756
Type: single nucleotide variant
Location: chr19:45354789 (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 536: a β-strand; the 'mediates interaction with mms19' region

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 xeroderma pigmentosum

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC2 p.Val536= Likely benign ★★ same residue
ERCC2 p.Val536Leu 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-val536met (accessed [today's date]).

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