Is DNMBP p.Thr1253Ser (c.3758C>G) pathogenic?

DNMBP p.Thr1253Ser (c.3758C>G) is classified Uncertain significance in DNMBP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: likely benign (0.1069); Ultra-rare (popmax 0.0102%, nfe).

How common is DNMBP p.Thr1253Ser (c.3758C>G) in the general population?

DNMBP p.Thr1253Ser (c.3758C>G) is ultra-rare (popmax 0.0102%, nfe) (gnomAD).

What do computational predictors say about DNMBP p.Thr1253Ser (c.3758C>G)?

AlphaMissense predicts likely benign (score 0.1069) — an in-silico prediction, not a clinical call.

DNMBP p.Thr1253Ser

c.3758C>G · rs913236673 · VCV2460585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1069 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1069	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -5.33	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 7.3	GERP 0.39, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 79 kb · p 0.11 · regional, not allelic
Overall
CADD	16.03	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 0.0102% European (non-Finnish) · 119/1,166,296 alleles

Filtering AF 0.00869% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00755% 120/1,589,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,801
Remaining individualsnot grpmax-eligible	0.00162%	61,572

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.Thr1253Ser
Coding: c.3758C>G
MANE Select: NM_015221
dbSNP: rs913236673
Type: single nucleotide variant
Location: chr10:99885727 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.91 · 7 PDB
Residue 1253: 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.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-thr1253ser (accessed [today's date]).

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