Is BHMT2 p.Leu262Pro (c.785T>C) pathogenic?

BHMT2 p.Leu262Pro (c.785T>C) is classified Uncertain significance in BHMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely pathogenic (0.7301); Ultra-rare (popmax 0.015%, amr).

How common is BHMT2 p.Leu262Pro (c.785T>C) in the general population?

BHMT2 p.Leu262Pro (c.785T>C) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about BHMT2 p.Leu262Pro (c.785T>C)?

AlphaMissense predicts likely pathogenic (score 0.7301) — an in-silico prediction, not a clinical call.

BHMT2 p.Leu262Pro

c.785T>C · VCV3991408

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7301 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7301	likely pathogenic
REVEL	0.37	indeterminate
SaProt	LLR -12.96	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 5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 19 kb · p 0.033 · regional, not allelic
Overall
CADD	23.7	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 0.015% Admixed American · 9/59,998 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00105% 17/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,666
European (non-Finnish)	0.000678%	147,488

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.Leu262Pro
Coding: c.785T>C
MANE Select: NM_017614
Type: single nucleotide variant
Location: chr5:79083631 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.82
Residue 262: 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-leu262pro (accessed [today's date]).

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