Is PCARE p.Ser1237fs (c.3708del) pathogenic?

PCARE p.Ser1237fs (c.3708del) is classified Uncertain significance in PCARE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-08). Very rare (popmax 0.004%, nfe).

How common is PCARE p.Ser1237fs (c.3708del) in the general population?

PCARE p.Ser1237fs (c.3708del) is very rare (popmax 0.004%, nfe) (gnomAD).

PCARE p.Ser1237fs

c.3708del · rs756746994 · VCV1040843

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.004%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP -0.66, phastCons 1
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% European (non-Finnish) · 46/1,149,194 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00274%

Overall 0.00315% 49/1,554,788 alleles · very rare exomes 42/1,402,940 · genomes 7/151,848 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.004%	24,982
Remaining individualsnot grpmax-eligible	0.00332%	30,133
African / African-American	0.00137%	72,984

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.Ser1237fs
Coding: c.3708del
MANE Select: NM_001029883
dbSNP: rs756746994
Type: Deletion
Location: chr2:29065028 (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 1237: the 'disordered' region; a UniProt-annotated variant site (found in a family with sensorineural hearing loss and retinal degeneration; likely pathogenic; the retinal involvement is more severe in double homozygotes also carrying a cep250 truncating variant)

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

Similar variants

PCARE p.Ala628fs Pathogenic ★★ same type
PCARE p.Arg767fs Pathogenic/Likely pathogenic ★★ same type
PCARE p.Asn316fs Pathogenic ★★ same type
PCARE p.Gln410fs Pathogenic ★★ same type
PCARE p.Glu1062fs Pathogenic/Likely pathogenic ★★ same type
PCARE p.Gly570fs Pathogenic ★★ same type
PCARE p.Gly964fs Likely pathogenic ★★ same type
PCARE p.His395fs Pathogenic/Likely pathogenic ★★ 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/pcare-p-ser1237fs (accessed [today's date]).

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