Is PITPNM3 p.Pro375= (c.1125G>A) pathogenic?

PITPNM3 p.Pro375= (c.1125G>A) is classified Benign/Likely benign in PITPNM3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-22). Ultra-rare (popmax 0.0421%, sas).

How common is PITPNM3 p.Pro375= (c.1125G>A) in the general population?

PITPNM3 p.Pro375= (c.1125G>A) is ultra-rare (popmax 0.0421%, sas) (gnomAD).

PITPNM3 p.Pro375=

c.1125G>A · rs201589217 · VCV1168753

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0421%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.3	GERP -2.8
Overall
CADD	0.655	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0421% South Asian · 37/87,932 alleles

Filtering AF 0.0314% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.0164% 261/1,590,738 alleles · ultra-rare exomes 229/1,438,412 · genomes 32/152,326 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.126%	792
South Asiangrpmax	0.0421%	2,377
Middle Eastern	0.0332%	3,015
Admixed American	0.0125%	8,026
European (non-Finnish)	0.0112%	8,925
Remaining individualsnot grpmax-eligible	0.00811%	12,329
East Asian	0.0023%	43,422

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: PITPNM3
Protein: p.Pro375=
Coding: c.1125G>A
MANE Select: NM_031220
dbSNP: rs201589217
Type: single nucleotide variant
Location: chr17:6474565 (GRCh38)
Gene constraint: LOEUF 0.354 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.73 · 1 PDB

Full PITPNM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PITPNM3 p.Pro375Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PITPNM3 c.2306+6T>A Uncertain significance ★★ same type
PITPNM3 c.351+3A>C Uncertain significance ★★ same type
PITPNM3 c.351+5G>A Uncertain significance ★★ same type
PITPNM3 c.*2957G>A Uncertain significance ★★ same type
PITPNM3 c.*3446G>T Uncertain significance ★★ same type
PITPNM3 c.*3452C>G Uncertain significance ★★ same type
PITPNM3 c.*3462G>C 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/pitpnm3-p-pro375 (accessed [today's date]).

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