Is ERCC3 p.Tyr139= (c.417C>T) pathogenic?

ERCC3 p.Tyr139= (c.417C>T) is classified Conflicting classifications of pathogenicity in ERCC3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0272%, nfe); Associated with trichothiodystrophy 2, photosensitive.

What condition is associated with ERCC3 p.Tyr139= (c.417C>T)?

ERCC3 p.Tyr139= (c.417C>T) is associated with trichothiodystrophy 2, photosensitive (ClinVar).

How common is ERCC3 p.Tyr139= (c.417C>T) in the general population?

ERCC3 p.Tyr139= (c.417C>T) is ultra-rare (popmax 0.0272%, nfe) (gnomAD).

ERCC3 p.Tyr139=

c.417C>T · rs529637184 · VCV721411

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0272%, nfe)

Conditions

trichothiodystrophy 2, photosensitive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -1.4, phastCons 1
Overall
CADD	7.766	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0272% European (non-Finnish) · 321/1,180,026 alleles

Filtering AF 0.0247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0238%

Overall 0.0208% 336/1,614,050 alleles · ultra-rare exomes 314/1,461,856 · genomes 22/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0272%	3,676
Remaining individualsnot grpmax-eligible	0.0144%	6,943
Admixed American	0.00833%	12,003
South Asian	0.0011%	91,080

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.Tyr139=
Coding: c.417C>T
MANE Select: NM_000122
dbSNP: rs529637184
Type: single nucleotide variant
Location: chr2:127292664 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 139: 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

Similar variants

ERCC3 c.1828-1G>C Likely pathogenic ★★ same condition
ERCC3 c.657+1G>A Likely pathogenic ★★ same condition
ERCC3 p.Arg109Ter Pathogenic/Likely 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
ERCC3 p.Arg574Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Gln388Ter 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-tyr139 (accessed [today's date]).

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