Is MESP2 p.Ser42Pro (c.124T>C) pathogenic?

MESP2 p.Ser42Pro (c.124T>C) is classified Uncertain significance in MESP2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-18). AlphaMissense: likely benign (0.2058); Very rare (popmax 6.52e-05%); Associated with spondylocostal dysostosis 2, autosomal recessive.

What condition is associated with MESP2 p.Ser42Pro (c.124T>C)?

MESP2 p.Ser42Pro (c.124T>C) is associated with spondylocostal dysostosis 2, autosomal recessive (ClinVar).

How common is MESP2 p.Ser42Pro (c.124T>C) in the general population?

MESP2 p.Ser42Pro (c.124T>C) is very rare (popmax 6.52e-05%) (gnomAD).

What do computational predictors say about MESP2 p.Ser42Pro (c.124T>C)?

AlphaMissense predicts likely benign (score 0.2058) — an in-silico prediction, not a clinical call.

MESP2 p.Ser42Pro

c.124T>C · VCV4057652

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.52e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

spondylocostal dysostosis 2, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.2058	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.1	GERP -4.7, phastCons 0.97
Regional constraint	o/e 1.18	unconstrained · MANE · 1,973 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	23.6	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 6.52e-05%

Overall 6.52e-05% 1/1,534,062 alleles · very rare exomes 1/1,381,730 · genomes 0/152,332 · joint denominator

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.Ser42Pro
Coding: c.124T>C
MANE Select: NM_001039958
Type: single nucleotide variant
Location: chr15:89776481 (GRCh38)
Gene constraint: LOEUF 1.656 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.92
Residue 42: the 'disordered' region

Full MESP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spondylocostal dysostosis 2, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MESP2 p.Ser42Ter Pathogenic/Likely pathogenic ★★ 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.Ser4Ter Pathogenic/Likely pathogenic ★★ same condition
MESP2 c.*107T>C Uncertain significance ★★ same condition
MESP2 p.Ala74Thr Uncertain significance ★★ ⚠ same condition
MESP2 p.Arg73Leu 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-ser42pro (accessed [today's date]).

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