Is MEIS2 p.Pro35= (c.105G>C) pathogenic?

MEIS2 p.Pro35= (c.105G>C) is classified Likely benign in MEIS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-15). Very rare (popmax 0.00935%, afr); Associated with cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies.

What condition is associated with MEIS2 p.Pro35= (c.105G>C)?

MEIS2 p.Pro35= (c.105G>C) is associated with cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies (ClinVar).

How common is MEIS2 p.Pro35= (c.105G>C) in the general population?

MEIS2 p.Pro35= (c.105G>C) is very rare (popmax 0.00935%, afr) (gnomAD).

MEIS2 p.Pro35=

c.105G>C · VCV3722135

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Conditions

cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.7	GERP 0.35, phastCons 1
Overall
CADD	15.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,874 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000434% 7/1,613,474 alleles · very rare exomes 4/1,461,464 · genomes 3/152,010 · joint denominator

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.Pro35=
Coding: c.105G>C
MANE Select: NM_170675
Type: single nucleotide variant
Location: chr15:37098107 (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

Disease context

cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MEIS2 p.Pro35Ser Uncertain significance ★ ⚠ same residue
MEIS2 p.Arg174Ter Pathogenic ★★ same condition
MEIS2 p.Arg219Ter Pathogenic/Likely pathogenic ★★ same condition
MEIS2 p.Asp169Asn Uncertain significance ★★ ⚠ same condition
MEIS2 p.Asp6Ala Uncertain significance ★★ ⚠ same condition
MEIS2 p.Ile33Val Uncertain significance ★★ ⚠ same condition
MEIS2 p.Pro416Arg Uncertain significance ★★ ⚠ same condition
MEIS2 c.13-19C>A Benign/Likely benign ★★ 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/meis2-p-pro35 (accessed [today's date]).

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