Is MESP2 p.Ser224Phe (c.671C>T) pathogenic?

MESP2 p.Ser224Phe (c.671C>T) is classified Benign in MESP2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.13); Common (popmax 8.34%, afr) — too common for a highly-penetrant pathogenic allele; Associated with spondylocostal dysostosis 2, autosomal recessive.

What condition is associated with MESP2 p.Ser224Phe (c.671C>T)?

MESP2 p.Ser224Phe (c.671C>T) is associated with spondylocostal dysostosis 2, autosomal recessive (ClinVar).

What do computational predictors say about MESP2 p.Ser224Phe (c.671C>T)?

AlphaMissense predicts likely benign (score 0.13) — an in-silico prediction, not a clinical call.

MESP2 p.Ser224Phe

Q: How common is MESP2 p.Ser224Phe (c.671C>T) in the general population?

MESP2 p.Ser224Phe (c.671C>T) is common (popmax 8.34%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.671C>T · rs71647807 · VCV257247

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.13 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.34%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondylocostal dysostosis 2, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.13	likely benign
REVEL	0.226	benign-leaning
SaProt	LLR -8.80	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 1	GERP 0.062
Regional constraint	o/e 1.18	unconstrained · MANE · 1,973 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	18.86	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 8.34% African / African-American · 6,184/74,116 alleles

Filtering AF 8.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.1%

Overall 0.441% 7,023/1,593,132 alleles · common exomes 3,374/1,440,830 · genomes 3,649/152,302 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.34%	12
Admixed American	0.622%	161
Remaining individualsnot grpmax-eligible	0.604%	166
Middle Eastern	0.265%	378
South Asian	0.0226%	4,433
European (non-Finnish)	0.00632%	15,829

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.Ser224Phe
Coding: c.671C>T
MANE Select: NM_001039958
dbSNP: rs71647807
Type: single nucleotide variant
Location: chr15:89777028 (GRCh38)
Gene constraint: LOEUF 1.656 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.92
Residue 224: the 'disordered' region; a UniProt-annotated variant site (in)

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.Ser224Pro Benign same residue
MESP2 p.Ser224Tyr Uncertain significance ★ ⚠ same residue
MESP2 p.Ser224= 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

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-ser224phe (accessed [today's date]).

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