Is ERCC3 p.Phe99Ser (c.296T>C) pathogenic?

ERCC3 p.Phe99Ser (c.296T>C) is classified Pathogenic in ERCC3 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-02). AlphaMissense: likely pathogenic (0.9972); Very rare (popmax 0.000847%, nfe); Associated with trichothiodystrophy 2, photosensitive.

What condition is associated with ERCC3 p.Phe99Ser (c.296T>C)?

ERCC3 p.Phe99Ser (c.296T>C) is associated with trichothiodystrophy 2, photosensitive, xeroderma pigmentosum group B (ClinVar).

How common is ERCC3 p.Phe99Ser (c.296T>C) in the general population?

ERCC3 p.Phe99Ser (c.296T>C) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about ERCC3 p.Phe99Ser (c.296T>C)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

ERCC3 p.Phe99Ser

c.296T>C · rs121913045 · VCV16583

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trichothiodystrophy 2, photosensitive

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic ✓ concordant with ClinVar
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -17.69	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 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	31.0	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 0.000847% European (non-Finnish) · 10/1,180,008 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000684% 10/1,461,624 alleles · very rare

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.Phe99Ser
Coding: c.296T>C
MANE Select: NM_000122
dbSNP: rs121913045
Type: single nucleotide variant
Location: chr2:127292785 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 99: a UniProt-annotated variant site (in xp-b; combined with features of cockayne syndrome; mild; reduced interaction with gtf2h4/p52 leads to low atpase stimulation and decreased dna duplex unwinding by tfiih; does not alter helicase activity; does not alter tfiih recruitment to dna damage; xpa is not recruited to dna damage by tfiih; nearly wild-type transcription activity by tfiih); an α-helix

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

Disease context

trichothiodystrophy 2, photosensitive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group B

Similar variants

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
ERCC3 p.Arg530Ter 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-phe99ser (accessed [today's date]).

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