Is NMBR p.Lys344Thr (c.1031A>C) pathogenic?

NMBR p.Lys344Thr (c.1031A>C) is classified Uncertain significance in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely benign (0.11); Ultra-rare (popmax 0.035%, amr).

How common is NMBR p.Lys344Thr (c.1031A>C) in the general population?

NMBR p.Lys344Thr (c.1031A>C) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about NMBR p.Lys344Thr (c.1031A>C)?

AlphaMissense predicts likely benign (score 0.11) — an in-silico prediction, not a clinical call.

NMBR p.Lys344Thr

c.1031A>C · rs947230038 · VCV2519623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.11 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.11	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -7.34	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 1.1	GERP 1.6, phastCons 0.85
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00021 · regional, not allelic
Overall
CADD	15.79	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

Grpmax group 0.035% Admixed American · 21/60,000 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0018% 29/1,613,964 alleles · ultra-rare exomes 14/1,461,806 · genomes 15/152,158 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,857
Remaining individualsnot grpmax-eligible	0.0096%	10,413
African / African-American	0.00267%	37,450

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: NMBR
Protein: p.Lys344Thr
Coding: c.1031A>C
MANE Select: NM_002511
dbSNP: rs947230038
Type: single nucleotide variant
Location: chr6:142075790 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 2 PDB

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

Similar variants

NMBR p.Arg310Trp Likely benign ★★ same type
NMBR p.Ile46= Benign/Likely benign ★★ same type
NMBR p.Ser358= Likely benign ★★ same type
NMBR p.Ala136Asp Uncertain significance ★ ⚠ same type
NMBR p.Ala179Val Uncertain significance ★ ⚠ same type
NMBR p.Ala185Val Uncertain significance ★ ⚠ same type
NMBR p.Ala236Thr Uncertain significance ★ ⚠ same type
NMBR p.Ala32Gly 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/nmbr-p-lys344thr (accessed [today's date]).

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