Is ERCC3 p.Met696Arg (c.2087T>G) pathogenic?

ERCC3 p.Met696Arg (c.2087T>G) is classified Uncertain significance in ERCC3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-10-05). AlphaMissense: likely pathogenic (0.814); Ultra-rare (popmax 0.0153%, nfe); Associated with xeroderma pigmentosum group B.

What condition is associated with ERCC3 p.Met696Arg (c.2087T>G)?

ERCC3 p.Met696Arg (c.2087T>G) is associated with xeroderma pigmentosum group B, xeroderma pigmentosum (ClinVar).

How common is ERCC3 p.Met696Arg (c.2087T>G) in the general population?

ERCC3 p.Met696Arg (c.2087T>G) is ultra-rare (popmax 0.0153%, nfe) (gnomAD).

What do computational predictors say about ERCC3 p.Met696Arg (c.2087T>G)?

AlphaMissense predicts likely pathogenic (score 0.814) — an in-silico prediction, not a clinical call.

ERCC3 p.Met696Arg

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

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

c.2087T>G · rs201806429 · VCV893870

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.814 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0153%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group B

Computational evidence

Protein change
AlphaMissense	0.814	likely pathogenic
REVEL	0.644	pathogenic-leaning
SaProt	LLR -16.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.79	acceptor gain · deltas
Pangolin	Δ0.33	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	35.0	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 0.0153% European (non-Finnish) · 181/1,180,030 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0126% 203/1,613,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0153%	6,519
Finnishnot grpmax-eligible	0.0141%	7,112
Remaining individualsnot grpmax-eligible	0.0128%	7,810
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
Admixed American	0.00333%	30,001

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.Met696Arg
Coding: c.2087T>G
MANE Select: NM_000122
dbSNP: rs201806429
Type: single nucleotide variant
Location: chr2:127259426 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 696: an α-helix; the helicase c-terminal domain

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

Disease context

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

Also linked: xeroderma pigmentosum

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC3 p.Met696Val Uncertain significance ★ ⚠ same residue
ERCC3 c.1828-1G>C Likely pathogenic ★★ same condition
ERCC3 c.471+1G>A Pathogenic ★★ same condition
ERCC3 c.657+1G>A Likely pathogenic ★★ same condition
ERCC3 p.Arg109Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Arg195Ter Pathogenic ★★ same condition
ERCC3 p.Arg425Ter Pathogenic ★★ same condition
ERCC3 p.Arg452Ter 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/ercc3-p-met696arg (accessed [today's date]).

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