Is PNMT p.Ala66Pro (c.196G>C) pathogenic?

PNMT p.Ala66Pro (c.196G>C) is classified Uncertain significance in PNMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). AlphaMissense: likely pathogenic (0.683); Absent from gnomAD v4.1.

How common is PNMT p.Ala66Pro (c.196G>C) in the general population?

PNMT p.Ala66Pro (c.196G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PNMT p.Ala66Pro (c.196G>C)?

AlphaMissense predicts likely pathogenic (score 0.683) — an in-silico prediction, not a clinical call.

PNMT p.Ala66Pro

c.196G>C · VCV4140622

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.683 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.683	likely pathogenic
REVEL	0.15	moderately benign-leaning
SaProt	LLR -13.76	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 0.92, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,910 bp · p 0.65 · regional, not allelic
Overall
CADD	26.0	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

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: PNMT
Protein: p.Ala66Pro
Coding: c.196G>C
MANE Select: NM_002686
Type: single nucleotide variant
Location: chr17:39668671 (GRCh38)
Gene constraint: LOEUF 1.458 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.64 · 44 PDB
Residue 66: an α-helix

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.Ala26Pro Uncertain significance ★ ⚠ same type
PNMT p.Ala41Val 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-ala66pro (accessed [today's date]).

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