Is ERCC4 p.Ser662Pro (c.1984T>C) pathogenic?

ERCC4 p.Ser662Pro (c.1984T>C) is classified Benign in ERCC4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.063); Common (popmax 20.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with xeroderma pigmentosum group F.

What condition is associated with ERCC4 p.Ser662Pro (c.1984T>C)?

ERCC4 p.Ser662Pro (c.1984T>C) is associated with xeroderma pigmentosum group F, Fanconi anemia complementation group Q, Cockayne syndrome (ClinVar).

What do computational predictors say about ERCC4 p.Ser662Pro (c.1984T>C)?

AlphaMissense predicts likely benign (score 0.063) — an in-silico prediction, not a clinical call.

ERCC4 p.Ser662Pro

Q: How common is ERCC4 p.Ser662Pro (c.1984T>C) in the general population?

ERCC4 p.Ser662Pro (c.1984T>C) is common (popmax 20.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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

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

c.1984T>C · rs2020955 · VCV134134

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.063 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 20.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group F

Computational evidence

Protein change
AlphaMissense	0.063	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -6.62	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 1.7	GERP 0.46, phastCons 0.42
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	4.506	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 20.7% African / African-American · 15,532/74,958 alleles

Filtering AF 20.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.3%

Overall 1.16% 18,745/1,613,574 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	20.7%	5
Admixed American	1.58%	63
Middle Eastern	1.57%	64
Remaining individualsnot grpmax-eligible	1.49%	67
Ashkenazi Jewishnot grpmax-eligible	1.06%	95
European (non-Finnish)	0.0724%	1,381
South Asian	0.0483%	2,070
Finnishnot grpmax-eligible	0.0437%	2,287
East Asian	0.00223%	44,890

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: ERCC4
Protein: p.Ser662Pro
Coding: c.1984T>C
MANE Select: NM_005236
dbSNP: rs2020955
Type: single nucleotide variant
Location: chr16:13944802 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 13 PDB
Residue 662: a UniProt-annotated variant site (in); the 'nuclease' region; the 'disordered' region

Full ERCC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Fanconi anemia complementation group Q Cockayne syndrome

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC4 c.1102+1G>T Likely pathogenic ★★ same condition
ERCC4 c.793-2A>G Pathogenic ★★ same condition
ERCC4 p.Arg20Ter Pathogenic ★★ same condition
ERCC4 p.Arg589Trp Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Arg689Ser Likely pathogenic ★★ same condition
ERCC4 p.Arg772Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Cys236Arg Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Cys723Ter 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/ercc4-p-ser662pro (accessed [today's date]).

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