Is CHSY1 p.Arg330Cys (c.988C>T) pathogenic?

CHSY1 p.Arg330Cys (c.988C>T) is classified Uncertain significance in CHSY1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: likely benign (0.1726); Ultra-rare (popmax 0.0267%, amr); Associated with temtamy preaxial brachydactyly syndrome.

What condition is associated with CHSY1 p.Arg330Cys (c.988C>T)?

CHSY1 p.Arg330Cys (c.988C>T) is associated with temtamy preaxial brachydactyly syndrome (ClinVar).

How common is CHSY1 p.Arg330Cys (c.988C>T) in the general population?

CHSY1 p.Arg330Cys (c.988C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about CHSY1 p.Arg330Cys (c.988C>T)?

AlphaMissense predicts likely benign (score 0.1726) — an in-silico prediction, not a clinical call.

CHSY1 p.Arg330Cys

c.988C>T · rs768914522 · VCV1025508

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

temtamy preaxial brachydactyly syndrome

Computational evidence

Protein change
AlphaMissense	0.1726	likely benign
REVEL	0.381	indeterminate
SaProt	LLR -11.33	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 58 kb · p 0.004 · regional, not allelic
Overall
CADD	29.9	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 0.0267% Admixed American · 16/60,004 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00359% 58/1,614,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,750
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00305%	32,779
African / African-American	0.00267%	37,458
East Asian	0.00223%	44,896

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.Arg330Cys
Coding: c.988C>T
MANE Select: NM_014918
dbSNP: rs768914522
Type: single nucleotide variant
Location: chr15:101178809 (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.Arg330His 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.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-arg330cys (accessed [today's date]).

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