Is CHSY1 p.Pro135Gln (c.404C>A) pathogenic?

CHSY1 p.Pro135Gln (c.404C>A) is classified Uncertain significance in CHSY1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-22). AlphaMissense: likely benign (0.1478); Ultra-rare (popmax 0.055%, amr); Associated with Inborn genetic diseases.

What condition is associated with CHSY1 p.Pro135Gln (c.404C>A)?

CHSY1 p.Pro135Gln (c.404C>A) is associated with Inborn genetic diseases, temtamy preaxial brachydactyly syndrome (ClinVar).

How common is CHSY1 p.Pro135Gln (c.404C>A) in the general population?

CHSY1 p.Pro135Gln (c.404C>A) is ultra-rare (popmax 0.055%, amr) (gnomAD).

What do computational predictors say about CHSY1 p.Pro135Gln (c.404C>A)?

AlphaMissense predicts likely benign (score 0.1478) — an in-silico prediction, not a clinical call.

CHSY1 p.Pro135Gln

c.404C>A · rs181832555 · VCV2074934

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1478 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.055%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1478	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -10.65	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 16 kb · p 0.0015 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.055% Admixed American · 33/60,014 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.00273% 44/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.055%	1,819
Remaining individualsnot grpmax-eligible	0.0144%	6,945
African / African-American	0.00133%	75,030
European (non-Finnish)	8.47e-05%	1,180,004

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.Pro135Gln
Coding: c.404C>A
MANE Select: NM_014918
dbSNP: rs181832555
Type: single nucleotide variant
Location: chr15:101235494 (GRCh38)
Gene constraint: LOEUF 0.357 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.20

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: temtamy preaxial brachydactyly syndrome

Similar variants

CHSY1 p.Ala263Ser Uncertain significance ★★ ⚠ same condition
CHSY1 p.Ala471Thr 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

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-pro135gln (accessed [today's date]).

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