Is CHSY1 p.Met780Val (c.2338A>G) pathogenic?

CHSY1 p.Met780Val (c.2338A>G) is classified Uncertain significance in CHSY1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0917); Ultra-rare (popmax 0.0143%, sas); Associated with Inborn genetic diseases.

What condition is associated with CHSY1 p.Met780Val (c.2338A>G)?

CHSY1 p.Met780Val (c.2338A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CHSY1 p.Met780Val (c.2338A>G) in the general population?

CHSY1 p.Met780Val (c.2338A>G) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about CHSY1 p.Met780Val (c.2338A>G)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

CHSY1 p.Met780Val

c.2338A>G · VCV4002817

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 58 kb · p 0.004 · regional, not allelic
Overall
CADD	18.75	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0143% South Asian · 13/90,820 alleles

Filtering AF 0.00847% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00663%

Overall 0.00103% 15/1,461,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	6,986
Remaining individualsnot grpmax-eligible	0.0032%	31,238

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.Met780Val
Coding: c.2338A>G
MANE Select: NM_014918
Type: single nucleotide variant
Location: chr15:101177459 (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.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
CHSY1 p.Arg423Gly Uncertain significance ★★ ⚠ same condition
CHSY1 p.Asn85Asp 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-met780val (accessed [today's date]).

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