Is DNMBP p.Pro22Leu (c.65C>T) pathogenic?

DNMBP p.Pro22Leu (c.65C>T) is classified Uncertain significance in DNMBP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely benign (0.2572); Ultra-rare (popmax 0.08%, afr).

How common is DNMBP p.Pro22Leu (c.65C>T) in the general population?

DNMBP p.Pro22Leu (c.65C>T) is ultra-rare (popmax 0.08%, afr) (gnomAD).

What do computational predictors say about DNMBP p.Pro22Leu (c.65C>T)?

AlphaMissense predicts likely benign (score 0.2572) — an in-silico prediction, not a clinical call.

DNMBP p.Pro22Leu

c.65C>T · rs116593720 · VCV2385429

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2572 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.08%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2572	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -11.60	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	30.0	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 0.08% African / African-American · 60/74,974 alleles

Filtering AF 0.0638% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.00632% 102/1,613,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.08%	1,250
Middle Eastern	0.066%	1,516
Admixed American	0.0133%	7,497
Remaining individualsnot grpmax-eligible	0.0112%	8,929
European (non-Finnish)	0.00186%	53,636
South Asian	0.0011%	91,068

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.Pro22Leu
Coding: c.65C>T
MANE Select: NM_015221
dbSNP: rs116593720
Type: single nucleotide variant
Location: chr10:99972060 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.91 · 7 PDB
Residue 22: the sh3 1 domain

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

Similar variants

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
DNMBP p.Cys1413Trp 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-pro22leu (accessed [today's date]).

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