Is CHSY1 p.Arg260Trp (c.778C>T) pathogenic?

CHSY1 p.Arg260Trp (c.778C>T) is classified Uncertain significance in CHSY1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: ambiguous (0.3897); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with CHSY1 p.Arg260Trp (c.778C>T)?

CHSY1 p.Arg260Trp (c.778C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHSY1 p.Arg260Trp (c.778C>T) in the general population?

CHSY1 p.Arg260Trp (c.778C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CHSY1 p.Arg260Trp (c.778C>T)?

AlphaMissense predicts ambiguous (score 0.3897) — an in-silico prediction, not a clinical call.

CHSY1 p.Arg260Trp

c.778C>T · VCV4615594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3897 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3897	ambiguous
REVEL	0.24	benign-leaning
SaProt	LLR -13.51	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.7	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 58 kb · p 0.004 · regional, not allelic
Overall
CADD	34.0	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 0.00401% African / African-American · 3/74,826 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00031% 5/1,613,804 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,942
European (non-Finnish)	0.000169%	590,002

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.Arg260Trp
Coding: c.778C>T
MANE Select: NM_014918
Type: single nucleotide variant
Location: chr15:101235120 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHSY1 p.Arg260= Likely benign ★★ same residue
CHSY1 p.Arg260Gln Uncertain significance ⚠ same residue
CHSY1 p.Ala471Thr Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg180His Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg229Trp Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg322His Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg336Cys Uncertain significance ★★ ⚠ same condition
CHSY1 p.Arg368His 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-arg260trp (accessed [today's date]).

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