Is ERCC4 p.Ser865Phe (c.2594C>T) pathogenic?

ERCC4 p.Ser865Phe (c.2594C>T) is classified Uncertain significance in ERCC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-28). AlphaMissense: likely benign (0.0867); Very rare (popmax 0.00988%, sas); Associated with xeroderma pigmentosum group F.

What condition is associated with ERCC4 p.Ser865Phe (c.2594C>T)?

ERCC4 p.Ser865Phe (c.2594C>T) is associated with xeroderma pigmentosum group F, XFE progeroid syndrome, Fanconi anemia complementation group Q (ClinVar).

How common is ERCC4 p.Ser865Phe (c.2594C>T) in the general population?

ERCC4 p.Ser865Phe (c.2594C>T) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about ERCC4 p.Ser865Phe (c.2594C>T)?

AlphaMissense predicts likely benign (score 0.0867) — an in-silico prediction, not a clinical call.

ERCC4 p.Ser865Phe

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

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

c.2594C>T · rs779099430 · VCV1710936

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group F

Computational evidence

Protein change
AlphaMissense	0.0867	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -8.74	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 4.9	GERP 2.1, phastCons 0.69
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	19.93	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 0.00988% South Asian · 9/91,072 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.000684% 10/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,119
European (non-Finnish)	8.47e-05%	1,180,032

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.Ser865Phe
Coding: c.2594C>T
MANE Select: NM_005236
dbSNP: rs779099430
Type: single nucleotide variant
Location: chr16:13948190 (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 865: an α-helix; the 'hhh2, dimerization with ercc1' 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: XFE progeroid syndrome Fanconi anemia complementation group Q

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-ser865phe (accessed [today's date]).

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