Is AHCY p.Ala397Val (c.1190C>T) pathogenic?

AHCY p.Ala397Val (c.1190C>T) is classified Uncertain significance in AHCY (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-14). AlphaMissense: likely benign (0.1849); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with AHCY p.Ala397Val (c.1190C>T)?

AHCY p.Ala397Val (c.1190C>T) is associated with Inborn genetic diseases, hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (ClinVar).

How common is AHCY p.Ala397Val (c.1190C>T) in the general population?

AHCY p.Ala397Val (c.1190C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about AHCY p.Ala397Val (c.1190C>T)?

AlphaMissense predicts likely benign (score 0.1849) — an in-silico prediction, not a clinical call.

AHCY p.Ala397Val

c.1190C>T · rs202122223 · VCV1522574

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1849 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1849	likely benign
REVEL	0.449	indeterminate
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 22 kb · p 2.6e-09 · regional, not allelic
Overall
CADD	22.5	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 0.005% Admixed American · 3/59,998 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000434% 7/1,613,436 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
European (non-Finnish)	0.000339%	295,011

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.Ala397Val
Coding: c.1190C>T
MANE Select: NM_000687
dbSNP: rs202122223
Type: single nucleotide variant
Location: chr20:34281143 (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 397: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

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-ala397val (accessed [today's date]).

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