Is DNMBP p.Leu975Arg (c.2924T>G) pathogenic?

DNMBP p.Leu975Arg (c.2924T>G) is classified Uncertain significance in DNMBP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-25). AlphaMissense: likely pathogenic (0.7076); Very rare (popmax 0.00136%, nfe).

How common is DNMBP p.Leu975Arg (c.2924T>G) in the general population?

DNMBP p.Leu975Arg (c.2924T>G) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about DNMBP p.Leu975Arg (c.2924T>G)?

AlphaMissense predicts likely pathogenic (score 0.7076) — an in-silico prediction, not a clinical call.

DNMBP p.Leu975Arg

c.2924T>G · VCV3841729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7076	likely pathogenic
REVEL	0.332	indeterminate
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 79 kb · p 0.11 · regional, not allelic
Overall
CADD	28.4	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 0.00136% European (non-Finnish) · 16/1,180,018 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00109% 16/1,461,830 alleles · very rare

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: DNMBP
Protein: p.Leu975Arg
Coding: c.2924T>G
MANE Select: NM_015221
Type: single nucleotide variant
Location: chr10:99896394 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.91 · 7 PDB
Residue 975: a UniProt-annotated variant site (in ctrct48)

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

Similar variants

DNMBP p.Leu975Phe Uncertain significance ★ ⚠ same residue
DNMBP p.Arg1326His Uncertain significance ★★ ⚠ same type
DNMBP p.Asn1560Lys Uncertain significance ★★ ⚠ same type
DNMBP p.Ser984Cys Uncertain significance ★★ ⚠ same type
DNMBP c.2554+8C>T Benign/Likely benign ★★ same type
DNMBP c.3156+7A>G Benign ★★ same type
DNMBP p.Asn373Lys Benign ★★ same type
DNMBP p.Asn961= Benign ★★ 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/dnmbp-p-leu975arg (accessed [today's date]).

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