Is CHM c.940+2T>C pathogenic?

CHM c.940+2T>C is classified Pathogenic in CHM (ClinVar, Single submitter, 2 submitters; last evaluated 2025-05-14). Very rare (popmax 0.000112%, nfe).

How common is CHM c.940+2T>C in the general population?

CHM c.940+2T>C is very rare (popmax 0.000112%, nfe) (gnomAD).

CHM c.940+2T>C

rs2147665632 · VCV1455558

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

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 in a haploinsufficient gene (ClinGen)
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.98	donor loss · deltas
Pangolin	Δ0.86	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.5	GERP 2.7, phastCons 1
Non-coding constraint	—	not assessed · autosomes only, so chrX has no window · absence ≠ unconstrained
Overall
CADD	24.0	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 0.000112% European (non-Finnish) · 1/889,694 alleles

Overall 9.19e-05% 1/1,088,430 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: CHM
Coding: c.940+2T>C
MANE Select: NM_000390
dbSNP: rs2147665632
Type: single nucleotide variant
Location: chrX:85957853 (GRCh38)
Structure: AlphaFold pLDDT 81.05

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

Similar variants

CHM c.116+1G>A Pathogenic/Likely pathogenic ★★ same type
CHM c.116+1G>T Pathogenic/Likely pathogenic ★★ same type
CHM c.1166+1G>A Pathogenic ★★ same type
CHM c.1166+1G>C Pathogenic ★★ same type
CHM c.1167-2A>G Pathogenic ★★ same type
CHM c.1244+1G>A Pathogenic ★★ same type
CHM c.1244+2T>A Pathogenic/Likely pathogenic ★★ same type
CHM c.1349+1G>T Pathogenic/Likely pathogenic ★★ 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/chm-c-940-plus-2t-c (accessed [today's date]).

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