Is CIROP c.2159+2T>A pathogenic?

CIROP c.2159+2T>A is classified Uncertain significance in CIROP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). Rare (popmax 0.124%, mid); Associated with trichothiodystrophy 1, photosensitive.

What condition is associated with CIROP c.2159+2T>A?

CIROP c.2159+2T>A is associated with trichothiodystrophy 1, photosensitive (ClinVar).

How common is CIROP c.2159+2T>A in the general population?

CIROP c.2159+2T>A is rare (popmax 0.124%, mid) (gnomAD).

CIROP c.2159+2T>A

VCV4277730

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.124%, mid)

Conditions

trichothiodystrophy 1, photosensitive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation 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	—	not assessed · no allele here is in the release
Pangolin	Δ0.37	loss · gain 0.02 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 8.7	GERP 2.2, phastCons 1
Non-coding constraint	Z 0.54	1 kb window · o/e 0.96 · regional · uncalibrated
Overall
CADD	24.5	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 0.124% Middle Eastern · 2/1,612 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00915%

Overall 0.00605% 25/413,362 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.124%	806
Remaining individualsnot grpmax-eligible	0.0108%	9,278
Admixed American	0.0088%	11,362
European (non-Finnish)	0.0084%	11,903

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: CIROP
Coding: c.2159+2T>A
MANE Select: NM_001354640
Type: single nucleotide variant
Location: chr14:23100500 (GRCh38)
Structure: AlphaFold pLDDT 73.73

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

Disease context

trichothiodystrophy 1, photosensitive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIROP c.988+1G>C Pathogenic ★ same condition
CIROP p.Glu376Lys Likely pathogenic ★ ⚠ same condition
CIROP p.Gln528Ter Likely pathogenic ★ same type
CIROP p.Arg22Ter Conflicting classifications of pathogenicity ★ same type
CIROP p.Gly180Arg Uncertain significance ★ ⚠ same type
CIROP p.Gly511Glu Uncertain significance ★ same type
CIROP p.Ser31Phe Conflicting classifications of pathogenicity ★ ⚠ same type
CIROP p.Tyr68Cys Uncertain significance ★ ⚠ same type

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/cirop-c-2159-plus-2t-a (accessed [today's date]).

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