Is ERCC1 p.Ser267Pro (c.799T>C) pathogenic?

ERCC1 p.Ser267Pro (c.799T>C) is classified Uncertain significance in ERCC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.2198); Rare (popmax 0.103%, mid); Associated with cerebrooculofacioskeletal syndrome 4.

What condition is associated with ERCC1 p.Ser267Pro (c.799T>C)?

ERCC1 p.Ser267Pro (c.799T>C) is associated with cerebrooculofacioskeletal syndrome 4 (ClinVar).

How common is ERCC1 p.Ser267Pro (c.799T>C) in the general population?

ERCC1 p.Ser267Pro (c.799T>C) is rare (popmax 0.103%, mid) (gnomAD).

What do computational predictors say about ERCC1 p.Ser267Pro (c.799T>C)?

AlphaMissense predicts likely benign (score 0.2198) — an in-silico prediction, not a clinical call.

ERCC1 p.Ser267Pro

c.799T>C · rs146256515 · VCV638523

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2198 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cerebrooculofacioskeletal syndrome 4

Computational evidence

Protein change
AlphaMissense	0.2198	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.16 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.103% Middle Eastern · 6/5,808 alleles

Filtering AF 0.0457% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0412%

Overall 0.0145% 234/1,613,652 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.179%	559
Middle Easterngrpmax	0.103%	968
South Asian	0.0582%	1,718
Remaining individualsnot grpmax-eligible	0.0352%	2,839
Admixed American	0.0217%	4,615
European (non-Finnish)	0.00703%	14,217
African / African-American	0.00534%	18,722

Ashkenazi Jewish 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.

Variant & gene context

Gene: ERCC1
Protein: p.Ser267Pro
Coding: c.799T>C
MANE Select: NM_001983
dbSNP: rs146256515
Type: single nucleotide variant
Location: chr19:45413721 (GRCh38)
Gene constraint: LOEUF 1.306 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 14 PDB
Residue 267: the 'hhh2, dimerization with ercc4/xpf' region

Full ERCC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebrooculofacioskeletal syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERCC1 p.Arg41Ter Pathogenic ★★ same condition
ERCC1 p.Arg156Gln Uncertain significance ★★ ⚠ same condition
ERCC1 p.Asn110Ser Uncertain significance ★★ ⚠ same condition
ERCC1 c.843+32G>A Benign/Likely benign ★★ same condition
POLR1G p.Thr282Ala Benign ★★ same condition
ERCC1 p.Glu62Ter Likely pathogenic ★ same condition
ERCC1 p.Phe231Leu Pathogenic ★ ⚠ same condition
ERCC1 c.843+32G>C Uncertain significance ★ 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/ercc1-p-ser267pro (accessed [today's date]).

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