Is MANBA p.Pro164Ser (c.490C>T) pathogenic?

MANBA p.Pro164Ser (c.490C>T) is classified Uncertain significance in MANBA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: ambiguous (0.4398); Very rare (popmax 0.00223%, eas).

How common is MANBA p.Pro164Ser (c.490C>T) in the general population?

MANBA p.Pro164Ser (c.490C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MANBA p.Pro164Ser (c.490C>T)?

AlphaMissense predicts ambiguous (score 0.4398) — an in-silico prediction, not a clinical call.

MANBA p.Pro164Ser

c.490C>T · VCV4968005

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
AlphaMissense	0.4398	ambiguous
REVEL	0.47	indeterminate
SaProt	LLR -10.43	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	24.6	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 0.00223% East Asian · 1/44,896 alleles

Overall 0.000124% 2/1,614,026 alleles · very rare exomes 1/1,461,822 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
European (non-Finnish)	8.47e-05%	1,179,990

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.Pro164Ser
Coding: c.490C>T
MANE Select: NM_005908
Type: single nucleotide variant
Location: chr4:102722930 (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

Similar variants

MANBA p.Pro164= Uncertain significance ★ same residue
MANBA c.1112+1G>T Likely pathogenic ★★ same type
MANBA c.1231-1G>A Likely pathogenic ★★ same type
MANBA c.1704+1G>T Likely pathogenic ★★ same type
MANBA c.2158-2A>G Pathogenic ★★ same type
MANBA c.273-1G>A Likely pathogenic ★★ same type
MANBA c.378+1G>A Likely pathogenic ★★ same type
MANBA c.549+1G>A Likely pathogenic ★★ 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/manba-p-pro164ser (accessed [today's date]).

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