Is AHCY p.Asp130= (c.390C>T) pathogenic?

AHCY p.Asp130= (c.390C>T) is classified Conflicting classifications of pathogenicity in AHCY (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.062%, nfe); Associated with hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase.

What condition is associated with AHCY p.Asp130= (c.390C>T)?

AHCY p.Asp130= (c.390C>T) is associated with hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (ClinVar).

How common is AHCY p.Asp130= (c.390C>T) in the general population?

AHCY p.Asp130= (c.390C>T) is ultra-rare (popmax 0.062%, 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.Asp130=

c.390C>T · rs143931269 · VCV788172

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.062%, 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 -9.9	GERP -4.1
Overall
CADD	0.265	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.062% European (non-Finnish) · 732/1,180,036 alleles

Filtering AF 0.0583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0568%

Overall 0.0492% 794/1,613,860 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.062%	1,612
Remaining individualsnot grpmax-eligible	0.0464%	2,154
African / African-American	0.0253%	3,948
Middle Eastern	0.0172%	5,806
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,402
Admixed American	0.005%	20,007
Finnishnot grpmax-eligible	0.00468%	21,348
East Asian	0.00446%	22,441
South Asian	0.0011%	91,056

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.Asp130=
Coding: c.390C>T
MANE Select: NM_000687
dbSNP: rs143931269
Type: single nucleotide variant
Location: chr20:34292413 (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 130: a UniProt-annotated variant site (in hmahchd; loss of adenosylhomocysteinase activity); a β-strand

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-asp130 (accessed [today's date]).

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