Is MEIS2 p.Pro35Ser (c.103C>T) pathogenic?

MEIS2 p.Pro35Ser (c.103C>T) is classified Uncertain significance in MEIS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-01). AlphaMissense: likely benign (0.0653); Very rare (popmax 0.00167%, amr).

How common is MEIS2 p.Pro35Ser (c.103C>T) in the general population?

MEIS2 p.Pro35Ser (c.103C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MEIS2 p.Pro35Ser (c.103C>T)?

AlphaMissense predicts likely benign (score 0.0653) — an in-silico prediction, not a clinical call.

MEIS2 p.Pro35Ser

c.103C>T · rs138503850 · VCV2645155

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0653	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -7.09	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,474 bp · p 0.4 · regional, not allelic
Overall
CADD	24.6	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 0.00167% Admixed American · 1/59,984 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00149% 24/1,613,744 alleles · very rare exomes 22/1,461,542 · genomes 2/152,202 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	31,945
Admixed Americangrpmax	0.00167%	59,984
European (non-Finnish)	0.00161%	62,102
Remaining individualsnot grpmax-eligible	0.0016%	62,490
South Asian	0.0011%	91,004

Finnish 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: MEIS2
Protein: p.Pro35Ser
Coding: c.103C>T
MANE Select: NM_170675
dbSNP: rs138503850
Type: single nucleotide variant
Location: chr15:37098109 (GRCh38)
Gene constraint: LOEUF 0.255 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.16 · 4 PDB

Full MEIS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MEIS2 p.Pro35= Likely benign ★ same residue
MEIS2 p.Arg174Ter Pathogenic ★★ same type
MEIS2 p.Arg219Ter Pathogenic/Likely pathogenic ★★ same type
MEIS2 p.Asp169Asn Uncertain significance ★★ ⚠ same type
MEIS2 p.Asp6Ala Uncertain significance ★★ ⚠ same type
MEIS2 p.His447Gln Uncertain significance ★★ ⚠ same type
MEIS2 p.Ile33Val Uncertain significance ★★ ⚠ same type
MEIS2 p.Leu154Ile 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/meis2-p-pro35ser (accessed [today's date]).

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