Is BHMT2 p.Arg265Ile (c.794G>T) pathogenic?

BHMT2 p.Arg265Ile (c.794G>T) is classified Uncertain significance in BHMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely pathogenic (0.8791); Very rare (popmax 0.000424%, nfe).

How common is BHMT2 p.Arg265Ile (c.794G>T) in the general population?

BHMT2 p.Arg265Ile (c.794G>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about BHMT2 p.Arg265Ile (c.794G>T)?

AlphaMissense predicts likely pathogenic (score 0.8791) — an in-silico prediction, not a clinical call.

BHMT2 p.Arg265Ile

c.794G>T · rs1317084891 · VCV2532304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8791	likely pathogenic · top 6% in BHMT2
REVEL	0.381	indeterminate
SaProt	LLR -10.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 19 kb · p 0.033 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000424% European (non-Finnish) · 5/1,179,916 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,704 alleles · very rare

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: BHMT2
Protein: p.Arg265Ile
Coding: c.794G>T
MANE Select: NM_017614
dbSNP: rs1317084891
Type: single nucleotide variant
Location: chr5:79083640 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.82
Residue 265: the hcy-binding domain

Full BHMT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BHMT2 p.Ala66Val Benign ★★ ⚠ same type
BHMT2 p.Ala126Gly Uncertain significance ★ ⚠ same type
BHMT2 p.Ala233Val Uncertain significance ★ ⚠ same type
BHMT2 p.Ala244Val Uncertain significance ★ ⚠ same type
BHMT2 p.Ala279Thr Uncertain significance ★ ⚠ same type
BHMT2 p.Ala98Thr Uncertain significance ★ ⚠ same type
BHMT2 p.Arg16Cys Uncertain significance ★ ⚠ same type
BHMT2 p.Arg16His Uncertain significance ★ ⚠ same type

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/bhmt2-p-arg265ile (accessed [today's date]).

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