Is AHCY p.Arg151Gln (c.452G>A) pathogenic?

AHCY p.Arg151Gln (c.452G>A) is classified Uncertain significance in AHCY (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-18). AlphaMissense: likely benign (0.0994); Very rare (popmax 0.00822%, nfe); Associated with hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase.

What condition is associated with AHCY p.Arg151Gln (c.452G>A)?

AHCY p.Arg151Gln (c.452G>A) is associated with hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (ClinVar).

How common is AHCY p.Arg151Gln (c.452G>A) in the general population?

AHCY p.Arg151Gln (c.452G>A) is very rare (popmax 0.00822%, nfe) (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.Arg151Gln (c.452G>A)?

AlphaMissense predicts likely benign (score 0.0994) — an in-silico prediction, not a clinical call.

AHCY p.Arg151Gln

c.452G>A · VCV4685623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00822%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Computational evidence

Protein change
AlphaMissense	0.0994	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -9.32	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 2.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 22 kb · p 2.6e-09 · regional, not allelic
Overall
CADD	24.9	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 0.00822% European (non-Finnish) · 97/1,179,916 alleles

Filtering AF 0.00689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00638% 103/1,614,044 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00822%	12,164
Admixed American	0.005%	20,008
African / African-American	0.00267%	37,516
East Asian	0.00223%	44,886

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.Arg151Gln
Coding: c.452G>A
MANE Select: NM_000687
Type: single nucleotide variant
Location: chr20:34291525 (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 151: a UniProt-annotated variant site (in hmahchd; loss of adenosylhomocysteinase activity)

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.Arg151= Likely benign ★ same residue
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

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-arg151gln (accessed [today's date]).

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