Is CHSY1 p.Pro45= (c.135C>T) pathogenic?

CHSY1 p.Pro45= (c.135C>T) is classified Likely benign in CHSY1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0755%, mid); Associated with temtamy preaxial brachydactyly syndrome.

What condition is associated with CHSY1 p.Pro45= (c.135C>T)?

CHSY1 p.Pro45= (c.135C>T) is associated with temtamy preaxial brachydactyly syndrome (ClinVar).

How common is CHSY1 p.Pro45= (c.135C>T) in the general population?

CHSY1 p.Pro45= (c.135C>T) is ultra-rare (popmax 0.0755%, mid) (gnomAD).

CHSY1 p.Pro45=

c.135C>T · rs921119348 · VCV720202

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0755%, mid)

Conditions

temtamy preaxial brachydactyly syndrome

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 -0.32	GERP -0.11, phastCons 0.001
Overall
CADD	10.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0755% Middle Eastern · 2/2,648 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00557%

Overall 0.00368% 41/1,115,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0755%	1,324
Remaining individualsnot grpmax-eligible	0.0111%	9,023
European (non-Finnish)	0.00374%	26,770
South Asian	0.0027%	36,996

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: CHSY1
Protein: p.Pro45=
Coding: c.135C>T
MANE Select: NM_014918
dbSNP: rs921119348
Type: single nucleotide variant
Location: chr15:101251322 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.20
Residue 45: the 'disordered' region

Full CHSY1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

temtamy preaxial brachydactyly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHSY1 p.Ala263Ser Uncertain significance ★★ ⚠ same condition
CHSY1 p.Ala61Val Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg180His Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg229Trp Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg233Trp Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg244Trp Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg322His Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg336Cys Uncertain significance ★★ ⚠ 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/chsy1-p-pro45 (accessed [today's date]).

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