Is MESP2 p.Pro57Arg (c.170C>G) pathogenic?

MESP2 p.Pro57Arg (c.170C>G) is classified Uncertain significance in MESP2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0809); Very rare (popmax 0.00493%, eas); Associated with Inborn genetic diseases.

What condition is associated with MESP2 p.Pro57Arg (c.170C>G)?

MESP2 p.Pro57Arg (c.170C>G) is associated with Inborn genetic diseases, spondylocostal dysostosis 2, autosomal recessive (ClinVar).

How common is MESP2 p.Pro57Arg (c.170C>G) in the general population?

MESP2 p.Pro57Arg (c.170C>G) is very rare (popmax 0.00493%, eas) (gnomAD).

What do computational predictors say about MESP2 p.Pro57Arg (c.170C>G)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

MESP2 p.Pro57Arg

c.170C>G · rs1257896833 · VCV990308

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00493%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -6.60	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 -0.66	GERP -4.3
Regional constraint	o/e 1.18	unconstrained · MANE · 1,973 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	5.848	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 0.00493% East Asian · 2/40,562 alleles

Filtering AF 0.000817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000306%

Overall 0.000391% 6/1,532,790 alleles · very rare exomes 6/1,380,426 · genomes 0/152,364 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00493%	20,281
Remaining individualsnot grpmax-eligible	0.00167%	59,738
European (non-Finnish)	0.000262%	381,828

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: MESP2
Protein: p.Pro57Arg
Coding: c.170C>G
MANE Select: NM_001039958
dbSNP: rs1257896833
Type: single nucleotide variant
Location: chr15:89776527 (GRCh38)
Gene constraint: LOEUF 1.656 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.92
Residue 57: the 'disordered' region

Full MESP2 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

Also linked: spondylocostal dysostosis 2, autosomal recessive

Similar variants

MESP2 p.Pro57Leu Uncertain significance ★ ⚠ same residue
MESP2 p.Pro57= Likely benign ★ same residue
MESP2 p.Gly77Ter Pathogenic/Likely pathogenic ★★ same condition
MESP2 p.Gly81Ter Pathogenic/Likely pathogenic ★★ same condition
MESP2 p.Ser39Ter Pathogenic/Likely pathogenic ★★ same condition
MESP2 p.Ser42Ter Pathogenic/Likely pathogenic ★★ same condition
MESP2 p.Ser4Ter Pathogenic/Likely pathogenic ★★ same condition
MESP2 c.*107T>C 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/mesp2-p-pro57arg (accessed [today's date]).

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