Is MESP2 p.Pro166= (c.498C>G) pathogenic?

MESP2 p.Pro166= (c.498C>G) is classified Benign/Likely benign in MESP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Low-frequency (popmax 4.27%, afr); Associated with spondylocostal dysostosis 2, autosomal recessive.

What condition is associated with MESP2 p.Pro166= (c.498C>G)?

MESP2 p.Pro166= (c.498C>G) is associated with spondylocostal dysostosis 2, autosomal recessive (ClinVar).

How common is MESP2 p.Pro166= (c.498C>G) in the general population?

MESP2 p.Pro166= (c.498C>G) is low-frequency (popmax 4.27%, afr) (gnomAD).

MESP2 p.Pro166=

c.498C>G · rs200336355 · VCV257240

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.27%, afr)

Conditions

spondylocostal dysostosis 2, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -3.7
Overall
CADD	6.314	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.27% African / African-American · 2,923/68,412 alleles

Filtering AF 4.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.09%

Overall 0.222% 3,235/1,459,394 alleles · low-frequency exomes 1,496/1,307,078 · genomes 1,739/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.27%	23
Remaining individualsnot grpmax-eligible	0.318%	314
Admixed American	0.271%	369
Middle Eastern	0.109%	915
South Asian	0.0172%	5,802
European (non-Finnish)	0.00126%	79,500

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.Pro166=
Coding: c.498C>G
MANE Select: NM_001039958
dbSNP: rs200336355
Type: single nucleotide variant
Location: chr15:89776855 (GRCh38)
Gene constraint: LOEUF 1.656 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.92
Residue 166: 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.Pro166Ser Uncertain significance ★ ⚠ 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
MESP2 p.Ala74Thr 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-pro166 (accessed [today's date]).

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