Is MANBA p.Thr765Pro (c.2293A>C) pathogenic?

MANBA p.Thr765Pro (c.2293A>C) is classified Uncertain significance in MANBA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.1141); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MANBA p.Thr765Pro (c.2293A>C)?

MANBA p.Thr765Pro (c.2293A>C) is associated with Inborn genetic diseases (ClinVar).

How common is MANBA p.Thr765Pro (c.2293A>C) in the general population?

MANBA p.Thr765Pro (c.2293A>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MANBA p.Thr765Pro (c.2293A>C)?

AlphaMissense predicts likely benign (score 0.1141) — an in-silico prediction, not a clinical call.

MANBA p.Thr765Pro

c.2293A>C · VCV4102875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1141	likely benign
REVEL	0.423	indeterminate
SaProt	LLR -12.20	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 3.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	18.79	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 8.47e-05% European (non-Finnish) · 1/1,180,056 alleles

Overall 6.2e-05% 1/1,614,108 alleles · very rare exomes 0/1,461,890 · genomes 1/152,218 · joint denominator

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: MANBA
Protein: p.Thr765Pro
Coding: c.2293A>C
MANE Select: NM_005908
Type: single nucleotide variant
Location: chr4:102634910 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.05
Residue 765: a UniProt-annotated variant site (in mansb; complete loss of enzyme activity)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MANBA p.Ala147Val Uncertain significance ★★ ⚠ same condition
MANBA p.Arg273Lys Uncertain significance ★★ ⚠ same condition
MANBA p.Asp713Val Uncertain significance ★★ ⚠ same condition
MANBA p.Asp813Val Uncertain significance ★★ ⚠ same condition
MANBA p.Cys761Ser Uncertain significance ★★ ⚠ same condition
MANBA p.Glu234Lys Uncertain significance ★★ ⚠ same condition
MANBA p.Glu848Lys Uncertain significance ★★ ⚠ same condition
MANBA p.Gly102Arg Uncertain significance ★★ ⚠ same condition

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/manba-p-thr765pro (accessed [today's date]).

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