Is ERCC2 c.183+2T>A pathogenic?

ERCC2 c.183+2T>A is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-02). Very rare (popmax 0.00458%, nfe); Associated with cerebrooculofacioskeletal syndrome 2.

What condition is associated with ERCC2 c.183+2T>A?

ERCC2 c.183+2T>A is associated with cerebrooculofacioskeletal syndrome 2, xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive (ClinVar).

How common is ERCC2 c.183+2T>A in the general population?

ERCC2 c.183+2T>A is very rare (popmax 0.00458%, nfe) (gnomAD).

ERCC2 c.183+2T>A

rs201127596 · VCV329529

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00458%, nfe)

Conditions

cerebrooculofacioskeletal syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.80	donor loss · deltas
Pangolin	Δ0.76	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Non-coding constraint	Z -0.41	1 kb window · o/e 1.03 · regional · uncalibrated
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 0.00458% European (non-Finnish) · 54/1,179,776 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00366% 59/1,613,062 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00458%	21,848
Admixed American	0.00334%	29,956
Remaining individualsnot grpmax-eligible	0.0032%	31,238
African / African-American	0.00134%	74,544

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
Coding: c.183+2T>A
MANE Select: NM_000400
dbSNP: rs201127596
Type: single nucleotide variant
Location: chr19:45369068 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB

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

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
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1544-1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1666-1G>A 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-c-183-plus-2t-a (accessed [today's date]).

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