Is AHCY p.Arg285Trp (c.853C>T) pathogenic?

AHCY p.Arg285Trp (c.853C>T) is classified Conflicting classifications of pathogenicity in AHCY (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1425); Rare (popmax 0.376%, afr); Associated with hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase.

What condition is associated with AHCY p.Arg285Trp (c.853C>T)?

AHCY p.Arg285Trp (c.853C>T) is associated with hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (ClinVar).

How common is AHCY p.Arg285Trp (c.853C>T) in the general population?

AHCY p.Arg285Trp (c.853C>T) is rare (popmax 0.376%, 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.Arg285Trp (c.853C>T)?

AlphaMissense predicts likely benign (score 0.1425) — an in-silico prediction, not a clinical call.

AHCY p.Arg285Trp

c.853C>T · rs116846245 · VCV715465

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1425 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.376%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Computational evidence

Protein change
AlphaMissense	0.1425	likely benign
REVEL	0.429	indeterminate
SaProt	LLR -11.58	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -1.3, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 22 kb · p 2.6e-09 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.376% African / African-American · 282/75,024 alleles

Filtering AF 0.34% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.326%

Overall 0.052% 839/1,614,142 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.35%	74
African / African-Americangrpmax	0.376%	266
Remaining individualsnot grpmax-eligible	0.12%	833
South Asian	0.0165%	6,072
East Asian	0.0134%	7,480
Admixed American	0.0133%	7,502
European (non-Finnish)	0.00441%	22,693

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg285Trp
Coding: c.853C>T
MANE Select: NM_000687
dbSNP: rs116846245
Type: single nucleotide variant
Location: chr20:34290552 (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 285: 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.Arg285Gln Uncertain significance ★ ⚠ 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-arg285trp (accessed [today's date]).

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