Is NMUR1 p.Tyr346Cys (c.1037A>G) pathogenic?

NMUR1 p.Tyr346Cys (c.1037A>G) is classified Uncertain significance in NMUR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-22). AlphaMissense: ambiguous (0.4088); Ultra-rare (popmax 0.0165%, mid).

How common is NMUR1 p.Tyr346Cys (c.1037A>G) in the general population?

NMUR1 p.Tyr346Cys (c.1037A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about NMUR1 p.Tyr346Cys (c.1037A>G)?

AlphaMissense predicts ambiguous (score 0.4088) — an in-silico prediction, not a clinical call.

NMUR1 p.Tyr346Cys

c.1037A>G · VCV3880132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4088 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4088	ambiguous
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -11.24	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.65, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 5,315 bp · p 0.033 · regional, not allelic
Overall
CADD	25.4	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000929% 15/1,614,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00167%	60,022
European (non-Finnish)	0.0011%	90,769

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: NMUR1
Protein: p.Tyr346Cys
Coding: c.1037A>G
MANE Select: NM_006056
Type: single nucleotide variant
Location: chr2:231525287 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.23 · 2 PDB
Residue 346: an α-helix

Full NMUR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NMUR1 p.Arg259Trp Benign/Likely benign ★★ same type
NMUR1 p.Ala176Val Uncertain significance ★ ⚠ same type
NMUR1 p.Ala236Val Uncertain significance ★ ⚠ same type
NMUR1 p.Ala25Thr Uncertain significance ★ ⚠ same type
NMUR1 p.Ala269Val Uncertain significance ★ ⚠ same type
NMUR1 p.Ala350Val Uncertain significance ★ ⚠ same type
NMUR1 p.Ala412Ser Uncertain significance ★ ⚠ same type
NMUR1 p.Arg159His 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/nmur1-p-tyr346cys (accessed [today's date]).

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