Is AHCY p.Pro323= (c.969G>A) pathogenic?

AHCY p.Pro323= (c.969G>A) is classified Likely benign in AHCY (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). Very rare (popmax 0.0089%, nfe); Associated with hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase.

What condition is associated with AHCY p.Pro323= (c.969G>A)?

AHCY p.Pro323= (c.969G>A) is associated with hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (ClinVar).

How common is AHCY p.Pro323= (c.969G>A) in the general population?

AHCY p.Pro323= (c.969G>A) is very rare (popmax 0.0089%, nfe) (gnomAD).

How is S-adenosylhomocysteine hydrolase deficiency inherited?

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

AHCY p.Pro323=

c.969G>A · rs746288986 · VCV2069585

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0089%, nfe)

Conditions

hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.68	GERP -4.1
Overall
CADD	4.604	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0089% European (non-Finnish) · 105/1,180,014 alleles

Filtering AF 0.00749% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.007%

Overall 0.00694% 112/1,613,840 alleles · very rare exomes 107/1,461,622 · genomes 5/152,218 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0089%	11,238
Admixed American	0.00667%	15,000
East Asian	0.00445%	22,449
South Asian	0.0011%	91,088

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.Pro323=
Coding: c.969G>A
MANE Select: NM_000687
dbSNP: rs746288986
Type: single nucleotide variant
Location: chr20:34290335 (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 323: 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.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-pro323 (accessed [today's date]).

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