Is ERCC2 p.Tyr339Ter (c.1017C>A) pathogenic?

ERCC2 p.Tyr339Ter (c.1017C>A) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-27). Very rare (popmax 0.00272%, afr); Associated with cerebrooculofacioskeletal syndrome 2.

What condition is associated with ERCC2 p.Tyr339Ter (c.1017C>A)?

ERCC2 p.Tyr339Ter (c.1017C>A) is associated with cerebrooculofacioskeletal syndrome 2, xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive (ClinVar).

How common is ERCC2 p.Tyr339Ter (c.1017C>A) in the general population?

ERCC2 p.Tyr339Ter (c.1017C>A) is very rare (popmax 0.00272%, afr) (gnomAD).

ERCC2 p.Tyr339Ter

c.1017C>A · rs1412068236 · VCV2169658

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00272%, afr)

Conditions

cerebrooculofacioskeletal syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 23
Splicing
SpliceAI	Δ0.28	donor gain · deltas
Constraint at this position
Conservation	phyloP -6.8	GERP -3.6
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00272% African / African-American · 2/73,464 alleles

Filtering AF 0.000452% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.000452% 7/1,548,648 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00272%	36,732
Remaining individualsnot grpmax-eligible	0.00166%	60,386
European (non-Finnish)	0.000347%	288,489

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: ERCC2
Protein: p.Tyr339Ter
Coding: c.1017C>A
MANE Select: NM_000400
dbSNP: rs1412068236
Type: single nucleotide variant
Location: chr19:45363844 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 339: an α-helix

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: xeroderma pigmentosum group D trichothiodystrophy 1, photosensitive

Similar variants

MAG p.Glu339Asp Uncertain significance ★★ ⚠ same residue
ERCC2 p.Tyr339= Likely benign ★★ same residue
ERCC2 p.Tyr339Asn Uncertain significance ★ ⚠ same residue
ERCC2 c.1238-1G>C Likely pathogenic ★★ same condition
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1378-1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1479+2T>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1480-1G>C 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/ercc2-p-tyr339ter (accessed [today's date]).

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