Is BHMT2 p.Arg57Cys (c.169C>T) pathogenic?

BHMT2 p.Arg57Cys (c.169C>T) is classified Uncertain significance in BHMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.0896); Ultra-rare (popmax 0.0441%, afr).

How common is BHMT2 p.Arg57Cys (c.169C>T) in the general population?

BHMT2 p.Arg57Cys (c.169C>T) is ultra-rare (popmax 0.0441%, afr) (gnomAD).

What do computational predictors say about BHMT2 p.Arg57Cys (c.169C>T)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

BHMT2 p.Arg57Cys

c.169C>T · rs141648685 · VCV3133829

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0441%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -13.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.33 · evaluated, not missing
Pangolin	Δ0.24	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -1	GERP -1.4
Regional constraint	o/e 0.90	unconstrained · MANE · 19 kb · p 0.033 · regional, not allelic
Overall
CADD	24.0	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 0.0441% African / African-American · 33/74,872 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.0036% 58/1,609,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0441%	2,269
Admixed American	0.0151%	6,642
East Asian	0.00893%	11,198
European (non-Finnish)	0.00102%	98,033

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.Arg57Cys
Coding: c.169C>T
MANE Select: NM_017614
dbSNP: rs141648685
Type: single nucleotide variant
Location: chr5:79079371 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.82
Residue 57: 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-arg57cys (accessed [today's date]).

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