Is DNMBP p.Ser593Leu (c.1778C>T) pathogenic?

DNMBP p.Ser593Leu (c.1778C>T) is classified Likely benign in DNMBP (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0861); Rare (popmax 0.589%, afr).

How common is DNMBP p.Ser593Leu (c.1778C>T) in the general population?

DNMBP p.Ser593Leu (c.1778C>T) is rare (popmax 0.589%, afr) (gnomAD).

What do computational predictors say about DNMBP p.Ser593Leu (c.1778C>T)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

DNMBP p.Ser593Leu

c.1778C>T · rs111969797 · VCV3035793

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.589%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -6.44	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 8.5	GERP 0.92, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 79 kb · p 0.11 · regional, not allelic
Overall
CADD	22.5	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 0.589% African / African-American · 442/75,074 alleles

Filtering AF 0.543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.525%

Overall 0.066% 1,066/1,614,216 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.589%	170
Middle Eastern	0.198%	505
Remaining individualsnot grpmax-eligible	0.106%	947
Admixed American	0.0816%	1,225
European (non-Finnish)	0.0419%	2,389
South Asian	0.0022%	45,541
Finnishnot grpmax-eligible	0.00156%	64,018

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.Ser593Leu
Coding: c.1778C>T
MANE Select: NM_015221
dbSNP: rs111969797
Type: single nucleotide variant
Location: chr10:99955696 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.91 · 7 PDB
Residue 593: the 'disordered' region; 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-ser593leu (accessed [today's date]).

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