Is NMBR p.Ile167Val (c.499A>G) pathogenic?

NMBR p.Ile167Val (c.499A>G) is classified Likely benign in NMBR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-01). AlphaMissense: likely benign (0.1933); Rare (popmax 0.391%, nfe).

How common is NMBR p.Ile167Val (c.499A>G) in the general population?

NMBR p.Ile167Val (c.499A>G) is rare (popmax 0.391%, nfe) (gnomAD).

What do computational predictors say about NMBR p.Ile167Val (c.499A>G)?

AlphaMissense predicts likely benign (score 0.1933) — an in-silico prediction, not a clinical call.

NMBR p.Ile167Val

c.499A>G · rs56126862 · VCV2656945

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1933 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.391%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1933	likely benign
REVEL	0.331	indeterminate
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.66, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 13 kb · p 0.00021 · regional, not allelic
Overall
CADD	19.61	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 0.391% European (non-Finnish) · 4,613/1,179,986 alleles

Filtering AF 0.381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.378%

Overall 0.307% 4,957/1,613,874 alleles · rare exomes 4,633/1,461,876 · genomes 324/151,998 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.391%	256
Remaining individualsnot grpmax-eligible	0.269%	372
Ashkenazi Jewishnot grpmax-eligible	0.138%	722
Finnishnot grpmax-eligible	0.0875%	1,143
African / African-American	0.0587%	1,702
Admixed American	0.0383%	2,609
Middle Eastern	0.0165%	6,060
South Asian	0.011%	9,106
East Asian	0.00223%	44,854

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.Ile167Val
Coding: c.499A>G
MANE Select: NM_002511
dbSNP: rs56126862
Type: single nucleotide variant
Location: chr6:142078827 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.77 · 2 PDB
Residue 167: 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.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-ile167val (accessed [today's date]).

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