Is PNMT p.Ala26Pro (c.76G>C) pathogenic?

PNMT p.Ala26Pro (c.76G>C) is classified Uncertain significance in PNMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: ambiguous (0.3746); Very rare (popmax 0.00186%, amr).

How common is PNMT p.Ala26Pro (c.76G>C) in the general population?

PNMT p.Ala26Pro (c.76G>C) is very rare (popmax 0.00186%, amr) (gnomAD).

What do computational predictors say about PNMT p.Ala26Pro (c.76G>C)?

AlphaMissense predicts ambiguous (score 0.3746) — an in-silico prediction, not a clinical call.

PNMT p.Ala26Pro

c.76G>C · VCV3935252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3746 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3746	ambiguous
REVEL	0.074	moderately benign-leaning
SaProt	LLR -14.19	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 0.83, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,910 bp · p 0.65 · regional, not allelic
Overall
CADD	21.9	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 0.00186% Admixed American · 1/53,892 alleles

Overall 0.000192% 3/1,561,124 alleles · very rare exomes 3/1,408,762 · genomes 0/152,362 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00186%	53,892
Remaining individualsnot grpmax-eligible	0.00165%	60,782
European (non-Finnish)	8.62e-05%	1,160,153

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: PNMT
Protein: p.Ala26Pro
Coding: c.76G>C
MANE Select: NM_002686
Type: single nucleotide variant
Location: chr17:39668551 (GRCh38)
Gene constraint: LOEUF 1.458 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.64 · 44 PDB

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

Similar variants

PNMT p.Ala41= Benign ★★ same type
PNMT p.Ala21Glu Uncertain significance ★ ⚠ same type
PNMT p.Ala227Thr Uncertain significance ★ ⚠ same type
PNMT p.Ala24Ser Uncertain significance ★ ⚠ same type
PNMT p.Ala41Val Uncertain significance ★ ⚠ same type
PNMT p.Ala66Pro Uncertain significance ★ ⚠ same type
PNMT p.Arg107His Uncertain significance ★ same type
PNMT p.Arg145His 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/pnmt-p-ala26pro (accessed [today's date]).

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