Is CHSY3 p.Ser856Arg (c.2566A>C) pathogenic?

CHSY3 p.Ser856Arg (c.2566A>C) is classified Uncertain significance in CHSY3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.9769); Ultra-rare (popmax 0.0266%, nfe).

How common is CHSY3 p.Ser856Arg (c.2566A>C) in the general population?

CHSY3 p.Ser856Arg (c.2566A>C) is ultra-rare (popmax 0.0266%, nfe) (gnomAD).

What do computational predictors say about CHSY3 p.Ser856Arg (c.2566A>C)?

AlphaMissense predicts likely pathogenic (score 0.9769) — an in-silico prediction, not a clinical call.

CHSY3 p.Ser856Arg

c.2566A>C · rs143863397 · VCV2600099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9769 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0266%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9769	likely pathogenic
REVEL	0.311	indeterminate
SaProt	LLR -10.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.76, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 390 bp · p 0.27 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0266% European (non-Finnish) · 314/1,179,860 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0232%

Overall 0.0204% 329/1,613,718 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0266%	3,758
Admixed American	0.00834%	11,997
Remaining individualsnot grpmax-eligible	0.008%	12,494
African / African-American	0.00668%	14,981

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: CHSY3
Protein: p.Ser856Arg
Coding: c.2566A>C
MANE Select: NM_175856
dbSNP: rs143863397
Type: single nucleotide variant
Location: chr5:130185708 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.97 · 2 PDB

Full CHSY3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHSY3 p.Ser856Thr Uncertain significance ★ ⚠ same residue
CHSY3 p.Ala141Thr Uncertain significance ★ ⚠ same type
CHSY3 p.Ala164Asp Uncertain significance ★ same type
CHSY3 p.Ala225Gly Uncertain significance ★ ⚠ same type
CHSY3 p.Ala53Val Uncertain significance ★ ⚠ same type
CHSY3 p.Ala793Thr Uncertain significance ★ ⚠ same type
CHSY3 p.Ala859Thr Uncertain significance ★ ⚠ same type
CHSY3 p.Arg112Gln Uncertain significance ★ ⚠ same type

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/chsy3-p-ser856arg (accessed [today's date]).

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