Is NNMT p.Ser64Phe (c.191C>T) pathogenic?

NNMT p.Ser64Phe (c.191C>T) is classified Uncertain significance in NNMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-25). AlphaMissense: likely pathogenic (0.7645); Ultra-rare (popmax 0.09%, amr).

How common is NNMT p.Ser64Phe (c.191C>T) in the general population?

NNMT p.Ser64Phe (c.191C>T) is ultra-rare (popmax 0.09%, amr) (gnomAD).

What do computational predictors say about NNMT p.Ser64Phe (c.191C>T)?

AlphaMissense predicts likely pathogenic (score 0.7645) — an in-silico prediction, not a clinical call.

NNMT p.Ser64Phe

c.191C>T · VCV3920561

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7645 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.09%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7645	likely pathogenic · top 9% in NNMT
REVEL	0.37	indeterminate
SaProt	LLR -14.08	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 4.4	GERP 1.8, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 16 kb · p 0.00057 · regional, not allelic
Overall
CADD	28.7	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

Grpmax group 0.09% Admixed American · 54/60,006 alleles

Filtering AF 0.0708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0639%

Overall 0.00359% 58/1,613,384 alleles · ultra-rare exomes 54/1,461,218 · genomes 4/152,166 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.09%	1,111
East Asian	0.00892%	11,217

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: NNMT
Protein: p.Ser64Phe
Coding: c.191C>T
MANE Select: NM_006169
Type: single nucleotide variant
Location: chr11:114297987 (GRCh38)
Gene constraint: LOEUF 1.306 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.11 · 33 PDB

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

Similar variants

NNMT p.Ala169Thr Uncertain significance ★ ⚠ same type
NNMT p.Ala179Ser Uncertain significance ★ ⚠ same type
NNMT p.Ala179Val Uncertain significance ★ ⚠ same type
NNMT p.Ala198Thr Uncertain significance ★ ⚠ same type
NNMT p.Ala257Val Uncertain significance ★ ⚠ same type
NNMT p.Arg18Gln Uncertain significance ★ ⚠ same type
NNMT p.Arg18Trp Uncertain significance ★ ⚠ same type
NNMT p.Arg218Gln 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/nnmt-p-ser64phe (accessed [today's date]).

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