Is AHCY p.Val366Met (c.1096G>A) pathogenic?

AHCY p.Val366Met (c.1096G>A) is classified Uncertain significance in AHCY (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-08). AlphaMissense: likely pathogenic (0.6421); Very rare (popmax 0.00133%, afr); Associated with hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase.

What condition is associated with AHCY p.Val366Met (c.1096G>A)?

AHCY p.Val366Met (c.1096G>A) is associated with hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (ClinVar).

How common is AHCY p.Val366Met (c.1096G>A) in the general population?

AHCY p.Val366Met (c.1096G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

How is S-adenosylhomocysteine hydrolase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AHCY p.Val366Met (c.1096G>A)?

AlphaMissense predicts likely pathogenic (score 0.6421) — an in-silico prediction, not a clinical call.

AHCY p.Val366Met

c.1096G>A · rs937156772 · VCV2059093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6421 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Computational evidence

Protein change
AlphaMissense	0.6421	likely pathogenic
REVEL	0.848	moderately pathogenic-leaning
SaProt	LLR -10.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 22 kb · p 2.6e-09 · regional, not allelic
Overall
CADD	28.2	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 0.00133% African / African-American · 1/75,064 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,834 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,064
European (non-Finnish)	0.000169%	589,998

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: AHCY
Protein: p.Val366Met
Coding: c.1096G>A
MANE Select: NM_000687
dbSNP: rs937156772
Type: single nucleotide variant
Location: chr20:34285511 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 98.21 · 10 PDB
Residue 366: a UniProt-annotated variant site (in hmahchd; loss of adenosylhomocysteinase activity); an α-helix

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

Disease context

hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For S-adenosylhomocysteine hydrolase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal

Similar variants

AHCY p.Arg49Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AHCY p.Asp86Gly Pathogenic/Likely pathogenic ★★ same condition
AHCY p.Tyr143Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AHCY c.-63A>G Uncertain significance ★★ same condition
AHCY c.*181C>T Uncertain significance ★★ same condition
AHCY p.Ala15Thr Uncertain significance ★★ ⚠ same condition
AHCY p.Ala16Pro Uncertain significance ★★ ⚠ same condition
AHCY p.Ala21Thr 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/ahcy-p-val366met (accessed [today's date]).

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