Is CHSY1 p.Val799Leu (c.2395G>T) pathogenic?

CHSY1 p.Val799Leu (c.2395G>T) is classified Uncertain significance in CHSY1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-28). AlphaMissense: likely benign (0.0727); Ultra-rare (popmax 0.0615%, afr); Associated with temtamy preaxial brachydactyly syndrome.

What condition is associated with CHSY1 p.Val799Leu (c.2395G>T)?

CHSY1 p.Val799Leu (c.2395G>T) is associated with temtamy preaxial brachydactyly syndrome (ClinVar).

How common is CHSY1 p.Val799Leu (c.2395G>T) in the general population?

CHSY1 p.Val799Leu (c.2395G>T) is ultra-rare (popmax 0.0615%, afr) (gnomAD).

What do computational predictors say about CHSY1 p.Val799Leu (c.2395G>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

CHSY1 p.Val799Leu

c.2395G>T · rs145722081 · VCV2085702

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0615%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

temtamy preaxial brachydactyly syndrome

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.39	GERP -4
Regional constraint	o/e 0.89	unconstrained · MANE · 58 kb · p 0.004 · regional, not allelic
Overall
CADD	5.43	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0615% African / African-American · 46/74,842 alleles

Filtering AF 0.0473% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0423%

Overall 0.00366% 59/1,612,560 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0615%	1,627
Admixed American	0.0134%	7,457
Remaining individualsnot grpmax-eligible	0.00481%	20,803
East Asian	0.00223%	44,894
European (non-Finnish)	8.48e-05%	1,179,654

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.Val799Leu
Coding: c.2395G>T
MANE Select: NM_014918
dbSNP: rs145722081
Type: single nucleotide variant
Location: chr15:101177402 (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.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-val799leu (accessed [today's date]).

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