Is HNMT p.Pro79Ser (c.235C>T) pathogenic?

HNMT p.Pro79Ser (c.235C>T) is classified Uncertain significance in HNMT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-21). AlphaMissense: likely benign (0.1288); Very rare (popmax 0.00222%, sas).

How common is HNMT p.Pro79Ser (c.235C>T) in the general population?

HNMT p.Pro79Ser (c.235C>T) is very rare (popmax 0.00222%, sas) (gnomAD).

What do computational predictors say about HNMT p.Pro79Ser (c.235C>T)?

AlphaMissense predicts likely benign (score 0.1288) — an in-silico prediction, not a clinical call.

HNMT p.Pro79Ser

c.235C>T · rs1441888966 · VCV2620229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1288 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00222%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1288	likely benign
REVEL	0.308	indeterminate
SaProt	LLR -10.96	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 50 kb · p 0.31 · 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 0.00222% South Asian · 2/89,908 alleles

Filtering AF 0.000369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000138%

Overall 0.000137% 2/1,456,120 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: HNMT
Protein: p.Pro79Ser
Coding: c.235C>T
MANE Select: NM_006895
dbSNP: rs1441888966
Type: single nucleotide variant
Location: chr2:138000962 (GRCh38)
Gene constraint: LOEUF 1.571 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.92 · 7 PDB

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

Similar variants

HNMT p.Leu208Pro Likely pathogenic ★★ same type
HNMT p.Gly48Ala Uncertain significance ★★ ⚠ same type
HNMT p.Met1Ile Uncertain significance ★★ same type
HNMT p.Gly60= Benign/Likely benign ★★ same type
HNMT p.Tyr186= Likely benign ★★ same type
HNMT p.Tyr147His Likely pathogenic ★ same type
HNMT c.137+2287G>A Uncertain significance ★ same type
HNMT p.Ala114Ser 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/hnmt-p-pro79ser (accessed [today's date]).

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