Is MANBA p.Arg143Ser (c.427C>A) pathogenic?

MANBA p.Arg143Ser (c.427C>A) is classified Uncertain significance in MANBA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.169); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with MANBA p.Arg143Ser (c.427C>A)?

MANBA p.Arg143Ser (c.427C>A) is associated with Inborn genetic diseases (ClinVar).

How common is MANBA p.Arg143Ser (c.427C>A) in the general population?

MANBA p.Arg143Ser (c.427C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MANBA p.Arg143Ser (c.427C>A)?

AlphaMissense predicts likely benign (score 0.169) — an in-silico prediction, not a clinical call.

MANBA p.Arg143Ser

c.427C>A · VCV3869920

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.169	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.7	GERP 1.4, phastCons 0.78
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	12.65	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 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,614,020 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
European (non-Finnish)	0.000678%	147,498

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.Arg143Ser
Coding: c.427C>A
MANE Select: NM_005908
Type: single nucleotide variant
Location: chr4:102722993 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.05

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.Arg143Cys Uncertain significance ★★ ⚠ same residue
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

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-arg143ser (accessed [today's date]).

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