Is CHSY3 p.Leu646Phe (c.1936C>T) pathogenic?

CHSY3 p.Leu646Phe (c.1936C>T) is classified Uncertain significance in CHSY3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: ambiguous (0.4288); Very rare (popmax 0.0035%, nfe).

How common is CHSY3 p.Leu646Phe (c.1936C>T) in the general population?

CHSY3 p.Leu646Phe (c.1936C>T) is very rare (popmax 0.0035%, nfe) (gnomAD).

What do computational predictors say about CHSY3 p.Leu646Phe (c.1936C>T)?

AlphaMissense predicts ambiguous (score 0.4288) — an in-silico prediction, not a clinical call.

CHSY3 p.Leu646Phe

c.1936C>T · VCV3833318

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4288 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0035%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4288	ambiguous
REVEL	0.306	indeterminate
SaProt	LLR -10.24	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 985 bp · p 0.77 · regional, not allelic
Overall
CADD	23.5	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 0.0035% European (non-Finnish) · 41/1,171,224 alleles

Filtering AF 0.0026% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00234%

Overall 0.00262% 42/1,604,314 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0035%	28,566
Remaining individualsnot grpmax-eligible	0.00161%	62,190

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.Leu646Phe
Coding: c.1936C>T
MANE Select: NM_175856
Type: single nucleotide variant
Location: chr5:130185078 (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.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
CHSY3 p.Arg145Trp 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-leu646phe (accessed [today's date]).

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