Is PCARE p.Pro433Ser (c.1297C>T) pathogenic?

PCARE p.Pro433Ser (c.1297C>T) is classified Conflicting classifications of pathogenicity in PCARE (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0813); Ultra-rare (popmax 0.0329%, mid); Associated with retinitis pigmentosa.

What condition is associated with PCARE p.Pro433Ser (c.1297C>T)?

PCARE p.Pro433Ser (c.1297C>T) is associated with retinitis pigmentosa, retinitis pigmentosa 54 (ClinVar).

How common is PCARE p.Pro433Ser (c.1297C>T) in the general population?

PCARE p.Pro433Ser (c.1297C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Retinitis pigmentosa inherited?

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

What do computational predictors say about PCARE p.Pro433Ser (c.1297C>T)?

AlphaMissense predicts likely benign (score 0.0813) — an in-silico prediction, not a clinical call.

PCARE p.Pro433Ser

c.1297C>T · rs200696965 · VCV335664

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0813 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.0813	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -6.03	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 0.37	GERP 0.67
Regional constraint	o/e 1.11	unconstrained · MANE · 9,389 bp · p 1.1e-05 · regional, not allelic
Overall
CADD	6.56	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.0392% 632/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.55%	64
Remaining individualsnot grpmax-eligible	0.107%	933
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.015%	6,665
European (non-Finnish)	0.00797%	12,553

Ashkenazi Jewish 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: PCARE
Protein: p.Pro433Ser
Coding: c.1297C>T
MANE Select: NM_001029883
dbSNP: rs200696965
Type: single nucleotide variant
Location: chr2:29072965 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 44.15 · 1 PDB
Residue 433: the 'disordered' region

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

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 54

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

PCARE c.3668+2T>C Likely pathogenic ★★ same condition
PCARE p.Arg1202Ter Pathogenic/Likely pathogenic ★★ same condition
PCARE p.Arg425Ter Pathogenic ★★ same condition
PCARE p.Arg613Ter Pathogenic ★★ same condition
PCARE p.Arg984Ter Pathogenic ★★ same condition
PCARE p.Gln1097Ter Pathogenic/Likely pathogenic ★★ same condition
PCARE p.Leu307Ter Pathogenic/Likely pathogenic ★★ same condition
PCARE p.Lys902Ter Pathogenic ★★ 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/pcare-p-pro433ser (accessed [today's date]).

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