Is MESP2 p.Pro258Ser (c.772C>T) pathogenic?

MESP2 p.Pro258Ser (c.772C>T) is classified Conflicting classifications of pathogenicity in MESP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-14). AlphaMissense: likely benign (0.107); Ultra-rare (popmax 0.0329%, mid).

How common is MESP2 p.Pro258Ser (c.772C>T) in the general population?

MESP2 p.Pro258Ser (c.772C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about MESP2 p.Pro258Ser (c.772C>T)?

AlphaMissense predicts likely benign (score 0.107) — an in-silico prediction, not a clinical call.

MESP2 p.Pro258Ser

c.772C>T · rs765025021 · VCV2162678

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.107 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.107	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.19	GERP -1.9
Regional constraint	o/e 1.18	unconstrained · MANE · 1,973 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	10.29	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00217% 35/1,612,872 alleles · ultra-rare exomes 30/1,460,652 · genomes 5/152,220 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
African / African-American	0.00534%	18,736
European (non-Finnish)	0.00237%	42,143
East Asian	0.00223%	44,878

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.Pro258Ser
Coding: c.772C>T
MANE Select: NM_001039958
dbSNP: rs765025021
Type: single nucleotide variant
Location: chr15:89777129 (GRCh38)
Gene constraint: LOEUF 1.656 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.92
Residue 258: the 'disordered' region

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

Similar variants

MESP2 p.Gly77Ter Pathogenic/Likely pathogenic ★★ same type
MESP2 p.Gly81Ter Pathogenic/Likely pathogenic ★★ same type
MESP2 p.Ser39Ter Pathogenic/Likely pathogenic ★★ same type
MESP2 p.Ser42Ter Pathogenic/Likely pathogenic ★★ same type
MESP2 p.Ser4Ter Pathogenic/Likely pathogenic ★★ same type
MESP2 c.*107T>C Uncertain significance ★★ same type
MESP2 p.Ala360Thr Uncertain significance ★★ ⚠ same type
MESP2 p.Ala74Thr Uncertain significance ★★ ⚠ same type

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-pro258ser (accessed [today's date]).

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