Is MESP2 p.Arg99Ser (c.295C>A) pathogenic?

MESP2 p.Arg99Ser (c.295C>A) is classified Uncertain significance in MESP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-30). AlphaMissense: likely pathogenic (0.7436); Very rare (popmax 0.00256%, eas).

How common is MESP2 p.Arg99Ser (c.295C>A) in the general population?

MESP2 p.Arg99Ser (c.295C>A) is very rare (popmax 0.00256%, eas) (gnomAD).

What do computational predictors say about MESP2 p.Arg99Ser (c.295C>A)?

AlphaMissense predicts likely pathogenic (score 0.7436) — an in-silico prediction, not a clinical call.

MESP2 p.Arg99Ser

c.295C>A · rs1482752912 · VCV1421300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7436 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00256%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7436	likely pathogenic · top 9% in MESP2
REVEL	0.408	indeterminate
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.6	GERP -0.009, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 1,973 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	23.0	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 0.00256% East Asian · 1/39,028 alleles

Filtering AF 0.000709% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000555%

Overall 0.00111% 17/1,530,644 alleles · very rare exomes 17/1,378,288 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00368%	27,142
East Asiangrpmax	0.00256%	39,028
South Asian	0.00122%	81,640
European (non-Finnish)	0.00122%	81,831

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg99Ser
Coding: c.295C>A
MANE Select: NM_001039958
dbSNP: rs1482752912
Type: single nucleotide variant
Location: chr15:89776652 (GRCh38)
Gene constraint: LOEUF 1.656 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.92
Residue 99: the bhlh domain

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-arg99ser (accessed [today's date]).

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