Is NNMT p.Ser212Phe (c.635C>T) pathogenic?

NNMT p.Ser212Phe (c.635C>T) is classified Uncertain significance in NNMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely benign (0.18); Absent from gnomAD v4.1.

How common is NNMT p.Ser212Phe (c.635C>T) in the general population?

NNMT p.Ser212Phe (c.635C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NNMT p.Ser212Phe (c.635C>T)?

AlphaMissense predicts likely benign (score 0.18) — an in-silico prediction, not a clinical call.

NNMT p.Ser212Phe

c.635C>T · VCV4558311

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.18 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.18	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.1, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 16 kb · p 0.00057 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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: NNMT
Protein: p.Ser212Phe
Coding: c.635C>T
MANE Select: NM_006169
Type: single nucleotide variant
Location: chr11:114312317 (GRCh38)
Gene constraint: LOEUF 1.306 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.11 · 33 PDB
Residue 212: a β-strand

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-ser212phe (accessed [today's date]).

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