Is AHCY p.Arg34Cys (c.100C>T) pathogenic?

AHCY p.Arg34Cys (c.100C>T) is classified Conflicting classifications of pathogenicity in AHCY (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-06-20). AlphaMissense: likely benign (0.1164); Ultra-rare (popmax 0.0547%, afr); Associated with Inborn genetic diseases.

What condition is associated with AHCY p.Arg34Cys (c.100C>T)?

AHCY p.Arg34Cys (c.100C>T) is associated with Inborn genetic diseases, hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (ClinVar).

How common is AHCY p.Arg34Cys (c.100C>T) in the general population?

AHCY p.Arg34Cys (c.100C>T) is ultra-rare (popmax 0.0547%, afr) (gnomAD).

What do computational predictors say about AHCY p.Arg34Cys (c.100C>T)?

AlphaMissense predicts likely benign (score 0.1164) — an in-silico prediction, not a clinical call.

AHCY p.Arg34Cys

c.100C>T · rs145239391 · VCV930024

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1164 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0547%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1164	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -3.97	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 4.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 22 kb · p 2.6e-09 · regional, not allelic
Overall
CADD	22.4	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 0.0547% African / African-American · 41/74,928 alleles

Filtering AF 0.0414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0368%

Overall 0.00459% 74/1,613,946 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0547%	1,828
Remaining individualsnot grpmax-eligible	0.0208%	4,806
Middle Eastern	0.0164%	6,082
Admixed American	0.005%	20,002
East Asian	0.00223%	44,890
European (non-Finnish)	0.00127%	78,669

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.Arg34Cys
Coding: c.100C>T
MANE Select: NM_000687
dbSNP: rs145239391
Type: single nucleotide variant
Location: chr20:34295514 (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 34: 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.Arg34= Likely benign ★ same residue
ASIP p.Arg34Lys 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

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-arg34cys (accessed [today's date]).

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