Is CHSY1 p.Arg233Gln (c.698G>A) pathogenic?

CHSY1 p.Arg233Gln (c.698G>A) is classified Uncertain significance in CHSY1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-30). AlphaMissense: likely benign (0.1056); Rare (popmax 0.139%, afr); Associated with temtamy preaxial brachydactyly syndrome.

What condition is associated with CHSY1 p.Arg233Gln (c.698G>A)?

CHSY1 p.Arg233Gln (c.698G>A) is associated with temtamy preaxial brachydactyly syndrome (ClinVar).

How common is CHSY1 p.Arg233Gln (c.698G>A) in the general population?

CHSY1 p.Arg233Gln (c.698G>A) is rare (popmax 0.139%, afr) (gnomAD).

What do computational predictors say about CHSY1 p.Arg233Gln (c.698G>A)?

AlphaMissense predicts likely benign (score 0.1056) — an in-silico prediction, not a clinical call.

CHSY1 p.Arg233Gln

c.698G>A · rs146924321 · VCV1381091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1056 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.139%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

temtamy preaxial brachydactyly syndrome

Computational evidence

Protein change
AlphaMissense	0.1056	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -10.03	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 317 bp · p 0.0024 · regional, not allelic
Overall
CADD	25.3	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 0.139% African / African-American · 104/74,884 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.109%

Overall 0.0127% 205/1,613,762 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.139%	720
East Asian	0.0334%	2,992
Admixed American	0.00833%	11,999
Remaining individualsnot grpmax-eligible	0.008%	12,494
European (non-Finnish)	0.00636%	15,731
South Asian	0.0011%	91,082

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.Arg233Gln
Coding: c.698G>A
MANE Select: NM_014918
dbSNP: rs146924321
Type: single nucleotide variant
Location: chr15:101235200 (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

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

Similar variants

CHSY1 p.Arg233Trp Uncertain significance ★★ ⚠ same residue
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.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-arg233gln (accessed [today's date]).

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