Is CHSY1 p.Lys111= (c.333G>A) pathogenic?

CHSY1 p.Lys111= (c.333G>A) is classified Benign/Likely benign in CHSY1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-29). Low-frequency (popmax 4.46%, amr); Associated with temtamy preaxial brachydactyly syndrome.

What condition is associated with CHSY1 p.Lys111= (c.333G>A)?

CHSY1 p.Lys111= (c.333G>A) is associated with temtamy preaxial brachydactyly syndrome (ClinVar).

How common is CHSY1 p.Lys111= (c.333G>A) in the general population?

CHSY1 p.Lys111= (c.333G>A) is low-frequency (popmax 4.46%, amr) (gnomAD).

CHSY1 p.Lys111=

c.333G>A · rs117481449 · VCV534523

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.46%, amr)

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 7.7	GERP 1.4, phastCons 1
Overall
CADD	13.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.46% Admixed American · 2,678/59,986 alleles

Filtering AF 4.32% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.27%

Overall 0.541% 8,717/1,610,168 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	4.46%	22
Remaining individualsnot grpmax-eligible	0.479%	209
European (non-Finnish)	0.455%	220
South Asian	0.247%	405
Amishnot grpmax-eligible	0.22%	455
Ashkenazi Jewishnot grpmax-eligible	0.122%	822
Middle Eastern	0.115%	866
African / African-American	0.0893%	1,119
Finnishnot grpmax-eligible	0.0597%	1,674
East Asian	0.00223%	44,872

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.Lys111=
Coding: c.333G>A
MANE Select: NM_014918
dbSNP: rs117481449
Type: single nucleotide variant
Location: chr15:101235565 (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-lys111 (accessed [today's date]).

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