Is PITPNM3 p.Pro147Ser (c.439C>T) pathogenic?

PITPNM3 p.Pro147Ser (c.439C>T) is classified Uncertain significance in PITPNM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-16). AlphaMissense: likely benign (0.0864); Very rare (popmax 0.00134%, afr); Associated with cone-rod dystrophy 5.

What condition is associated with PITPNM3 p.Pro147Ser (c.439C>T)?

PITPNM3 p.Pro147Ser (c.439C>T) is associated with cone-rod dystrophy 5 (ClinVar).

How common is PITPNM3 p.Pro147Ser (c.439C>T) in the general population?

PITPNM3 p.Pro147Ser (c.439C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Cone rod dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PITPNM3 p.Pro147Ser (c.439C>T)?

AlphaMissense predicts likely benign (score 0.0864) — an in-silico prediction, not a clinical call.

PITPNM3 p.Pro147Ser

c.439C>T · VCV4079667

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0864 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cone-rod dystrophy 5

Computational evidence

Protein change
AlphaMissense	0.0864	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -4.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 78 kb · p 0.0093 · regional, not allelic
Overall
CADD	23.8	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 0.00134% African / African-American · 1/74,464 alleles

Overall 0.00133% 2/150,842 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,464
European (non-Finnish)	8.48e-05%	1,179,594

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.Pro147Ser
Coding: c.439C>T
MANE Select: NM_031220
Type: single nucleotide variant
Location: chr17:6483665 (GRCh38)
Gene constraint: LOEUF 0.354 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.73 · 1 PDB
Residue 147: an α-helix

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

Disease context

cone-rod dystrophy 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

PITPNM3 p.Pro147Leu Uncertain significance ★★ ⚠ same residue
PITPNM3 p.Pro147= Benign/Likely benign ★★ same residue
PITPNM3 c.*2957G>A Uncertain significance ★★ same condition
PITPNM3 c.*3446G>T Uncertain significance ★★ same condition
PITPNM3 c.*3452C>G Uncertain significance ★★ same condition
PITPNM3 c.*3462G>C Uncertain significance ★★ same condition
PITPNM3 p.Ala305Ser Uncertain significance ★★ ⚠ same condition
PITPNM3 p.Ala837Val Uncertain significance ★★ ⚠ 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/pitpnm3-p-pro147ser (accessed [today's date]).

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