Is PITX3 p.Pro14= (c.42T>C) pathogenic?

PITX3 p.Pro14= (c.42T>C) is classified Uncertain significance in PITX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2015-10-15). Ultra-rare (popmax 0.0491%, eas).

How common is PITX3 p.Pro14= (c.42T>C) in the general population?

PITX3 p.Pro14= (c.42T>C) is ultra-rare (popmax 0.0491%, eas) (gnomAD).

PITX3 p.Pro14=

c.42T>C · rs367562631 · VCV283807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0491%, eas)

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -1.4	GERP -3.7
Overall
CADD	10.01	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0491% East Asian · 22/44,766 alleles

Filtering AF 0.0332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.028%

Overall 0.0038% 61/1,606,370 alleles · ultra-rare exomes 55/1,454,018 · genomes 6/152,352 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0578%	1,729
East Asiangrpmax	0.0491%	2,035
Admixed American	0.00336%	29,743
European (non-Finnish)	8.48e-05%	1,178,600

Remaining individuals 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: PITX3
Protein: p.Pro14=
Coding: c.42T>C
MANE Select: NM_005029
dbSNP: rs367562631
Type: single nucleotide variant
Location: chr10:102232039 (GRCh38)

Full PITX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/pitx3-p-pro14 (accessed [today's date]).

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