Is NMBR p.Ala236Thr (c.706G>A) pathogenic?

NMBR p.Ala236Thr (c.706G>A) is classified Uncertain significance in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-06). AlphaMissense: likely pathogenic (0.5794); Very rare (popmax 0.00133%, afr).

How common is NMBR p.Ala236Thr (c.706G>A) in the general population?

NMBR p.Ala236Thr (c.706G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about NMBR p.Ala236Thr (c.706G>A)?

AlphaMissense predicts likely pathogenic (score 0.5794) — an in-silico prediction, not a clinical call.

NMBR p.Ala236Thr

c.706G>A · rs748910779 · VCV2213336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5794	likely pathogenic
REVEL	0.351	indeterminate
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00021 · regional, not allelic
Overall
CADD	26.8	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 0.00133% African / African-American · 1/74,970 alleles

Overall 0.000124% 2/1,613,062 alleles · very rare exomes 2/1,460,878 · genomes 0/152,184 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,474
African / African-Americangrpmax	0.00133%	74,970

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala236Thr
Coding: c.706G>A
MANE Select: NM_002511
dbSNP: rs748910779
Type: single nucleotide variant
Location: chr6:142078620 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 2 PDB
Residue 236: an α-helix

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.Ala32Gly Uncertain significance ★ ⚠ same type
NMBR p.Ala369Val 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-ala236thr (accessed [today's date]).

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