Is MAPRE2 p.Gln280Pro (c.839A>C) pathogenic?

MAPRE2 p.Gln280Pro (c.839A>C) is classified Uncertain significance in MAPRE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.9681); Very rare (popmax 0.00446%, eas).

How common is MAPRE2 p.Gln280Pro (c.839A>C) in the general population?

MAPRE2 p.Gln280Pro (c.839A>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about MAPRE2 p.Gln280Pro (c.839A>C)?

AlphaMissense predicts likely pathogenic (score 0.9681) — an in-silico prediction, not a clinical call.

MAPRE2 p.Gln280Pro

c.839A>C · VCV4534930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9681	likely pathogenic
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -15.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 38 kb · p 3.7e-06 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000372% 6/1,614,234 alleles · very rare exomes 6/1,461,844 · genomes 0/152,390 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,442
European (non-Finnish)	0.000339%	295,006

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: MAPRE2
Protein: p.Gln280Pro
Coding: c.839A>C
MANE Select: NM_014268
Type: single nucleotide variant
Location: chr18:35132120 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 75.12
Residue 280: the eb1 c-terminal domain; the 'dctn1-binding' region; the 'apc-binding' region

Full MAPRE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPRE2 p.Arg143Cys Pathogenic/Likely pathogenic ★★ same type
MAPRE2 p.Glu318Lys Uncertain significance ★★ ⚠ same type
MAPRE2 p.Ser28Ter Uncertain significance ★★ same type
MAPRE2 c.250+8A>T Benign/Likely benign ★★ same type
MAPRE2 p.Gly260= Benign ★★ same type
MAPRE2 p.His282= Benign/Likely benign ★★ same type
MAPRE2 p.Pro322= Benign ★★ same type
MAPRE2 p.Arg173Gln 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/mapre2-p-gln280pro (accessed [today's date]).

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