Is BHMT2 p.Phe63Leu (c.189C>G) pathogenic?

BHMT2 p.Phe63Leu (c.189C>G) is classified Uncertain significance in BHMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-06). AlphaMissense: likely pathogenic (0.9645); Absent from gnomAD v4.1.

How common is BHMT2 p.Phe63Leu (c.189C>G) in the general population?

BHMT2 p.Phe63Leu (c.189C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BHMT2 p.Phe63Leu (c.189C>G)?

AlphaMissense predicts likely pathogenic (score 0.9645) — an in-silico prediction, not a clinical call.

BHMT2 p.Phe63Leu

c.189C>G · rs2530848547 · VCV2480982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9645 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9645	likely pathogenic · top 1% in BHMT2
REVEL	0.37	indeterminate
SaProt	LLR -10.30	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 2.6	GERP 1.7, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 19 kb · p 0.033 · regional, not allelic
Overall
CADD	25.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BHMT2
Protein: p.Phe63Leu
Coding: c.189C>G
MANE Select: NM_017614
dbSNP: rs2530848547
Type: single nucleotide variant
Location: chr5:79079391 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.82
Residue 63: 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-phe63leu (accessed [today's date]).

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