Is CHSY1 p.Ser522= (c.1566G>A) pathogenic?

CHSY1 p.Ser522= (c.1566G>A) is classified Benign/Likely benign in CHSY1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Low-frequency (popmax 2.25%, afr); Associated with temtamy preaxial brachydactyly syndrome.

What condition is associated with CHSY1 p.Ser522= (c.1566G>A)?

CHSY1 p.Ser522= (c.1566G>A) is associated with temtamy preaxial brachydactyly syndrome (ClinVar).

How common is CHSY1 p.Ser522= (c.1566G>A) in the general population?

CHSY1 p.Ser522= (c.1566G>A) is low-frequency (popmax 2.25%, afr) (gnomAD).

CHSY1 p.Ser522=

c.1566G>A · rs74784454 · VCV786869

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.25%, afr)

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 -3.6	GERP -3.8
Overall
CADD	0.196	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.25% African / African-American · 1,685/75,040 alleles

Filtering AF 2.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.12%

Overall 0.178% 2,867/1,614,190 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.25%	45
Middle Eastern	0.462%	216
Remaining individualsnot grpmax-eligible	0.261%	384
Admixed American	0.198%	504
South Asian	0.0889%	1,124
European (non-Finnish)	0.0658%	1,521
Finnishnot grpmax-eligible	0.0203%	4,926
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,890

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.Ser522=
Coding: c.1566G>A
MANE Select: NM_014918
dbSNP: rs74784454
Type: single nucleotide variant
Location: chr15:101178231 (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.Ser522Pro 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-ser522 (accessed [today's date]).

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