Is MAPRE2 p.Val290Met (c.868G>A) pathogenic?

MAPRE2 p.Val290Met (c.868G>A) is classified Conflicting classifications of pathogenicity in MAPRE2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-25). AlphaMissense: likely benign (0.2504); Very rare (popmax 0.0089%, nfe); Associated with skin creases, congenital symmetric circumferential, 2.

What condition is associated with MAPRE2 p.Val290Met (c.868G>A)?

MAPRE2 p.Val290Met (c.868G>A) is associated with skin creases, congenital symmetric circumferential, 2 (ClinVar).

How common is MAPRE2 p.Val290Met (c.868G>A) in the general population?

MAPRE2 p.Val290Met (c.868G>A) is very rare (popmax 0.0089%, nfe) (gnomAD).

What do computational predictors say about MAPRE2 p.Val290Met (c.868G>A)?

AlphaMissense predicts likely benign (score 0.2504) — an in-silico prediction, not a clinical call.

MAPRE2 p.Val290Met

Q: How is Multiple benign circumferential skin creases on limbs inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.868G>A · VCV3543249

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0089%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

skin creases, congenital symmetric circumferential, 2

Computational evidence

Protein change
AlphaMissense	0.2504	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -9.19	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 8.7	GERP -0.29, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 38 kb · p 3.7e-06 · regional, not allelic
Overall
CADD	23.7	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 0.0089% European (non-Finnish) · 105/1,180,032 alleles

Filtering AF 0.00749% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.007%

Overall 0.00669% 108/1,614,064 alleles · very rare exomes 106/1,461,852 · genomes 2/152,212 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0089%	11,238
East Asian	0.00223%	44,898
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,926

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.Val290Met
Coding: c.868G>A
MANE Select: NM_014268
Type: single nucleotide variant
Location: chr18:35132149 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 75.12
Residue 290: 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

Disease context

skin creases, congenital symmetric circumferential, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple benign circumferential skin creases on limbs (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

MAPRE2 p.Arg143Cys Pathogenic/Likely pathogenic ★★ same condition
MAPRE2 p.Arg173Gln Likely pathogenic ★ same condition
MAPRE2 p.Ala123Thr Uncertain significance ★ same condition
MAPRE2 p.Arg127Gln Uncertain significance ★ ⚠ same condition
MAPRE2 p.Arg173Ter Conflicting classifications of pathogenicity ★ ⚠ same condition
MAPRE2 p.Gly24Arg Uncertain significance ★ ⚠ same condition
MAPRE2 p.Tyr158Cys Uncertain significance ★ ⚠ same condition
MAPRE2 p.Asn68Ser Pathogenic 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/mapre2-p-val290met (accessed [today's date]).

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