Is CHSY3 p.Ser486Arg (c.1458C>A) pathogenic?

CHSY3 p.Ser486Arg (c.1458C>A) is classified Uncertain significance in CHSY3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-02). AlphaMissense: likely pathogenic (0.6381); Very rare (popmax 0.00549%, sas).

How common is CHSY3 p.Ser486Arg (c.1458C>A) in the general population?

CHSY3 p.Ser486Arg (c.1458C>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about CHSY3 p.Ser486Arg (c.1458C>A)?

AlphaMissense predicts likely pathogenic (score 0.6381) — an in-silico prediction, not a clinical call.

CHSY3 p.Ser486Arg

c.1458C>A · rs374972484 · VCV2556057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6381 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6381	likely pathogenic
REVEL	0.007	strongly benign-leaning
SaProt	LLR -5.46	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP 0.35, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 985 bp · p 0.77 · regional, not allelic
Overall
CADD	15.98	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 0.00549% South Asian · 5/91,016 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.000497% 8/1,611,192 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,203
Remaining individualsnot grpmax-eligible	0.00481%	20,809

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.Ser486Arg
Coding: c.1458C>A
MANE Select: NM_175856
dbSNP: rs374972484
Type: single nucleotide variant
Location: chr5:130184600 (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.Ser486Thr 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-ser486arg (accessed [today's date]).

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