Is PCARE p.Arg656Ser (c.1968G>T) pathogenic?

PCARE p.Arg656Ser (c.1968G>T) is classified Conflicting classifications of pathogenicity in PCARE (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-15). AlphaMissense: likely benign (0.2182); Rare (popmax 0.148%, mid); Associated with retinitis pigmentosa.

What condition is associated with PCARE p.Arg656Ser (c.1968G>T)?

PCARE p.Arg656Ser (c.1968G>T) is associated with retinitis pigmentosa, retinitis pigmentosa 54 (ClinVar).

How common is PCARE p.Arg656Ser (c.1968G>T) in the general population?

PCARE p.Arg656Ser (c.1968G>T) is rare (popmax 0.148%, 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.Arg656Ser (c.1968G>T)?

AlphaMissense predicts likely benign (score 0.2182) — an in-silico prediction, not a clinical call.

PCARE p.Arg656Ser

c.1968G>T · rs201980758 · VCV335652

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2182 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.2182	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -5.16	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 -2.3
Regional constraint	o/e 1.11	unconstrained · MANE · 9,389 bp · p 1.1e-05 · regional, not allelic
Overall
CADD	8.013	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 0.148% Middle Eastern · 9/6,062 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.0182% 293/1,614,220 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	674
Ashkenazi Jewishnot grpmax-eligible	0.105%	955
Admixed American	0.0766%	1,305
Remaining individualsnot grpmax-eligible	0.0592%	1,689
European (non-Finnish)	0.0142%	7,066
African / African-American	0.004%	25,019

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.Arg656Ser
Coding: c.1968G>T
MANE Select: NM_001029883
dbSNP: rs201980758
Type: single nucleotide variant
Location: chr2:29072294 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 44.15 · 1 PDB

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-arg656ser (accessed [today's date]).

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