Is CARF p.Pro454= (c.1362C>T) pathogenic?

CARF p.Pro454= (c.1362C>T) is classified Benign in CARF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-05-09). Common (popmax 8.43%, afr) — too common for a highly-penetrant pathogenic allele.

CARF p.Pro454=

Q: How common is CARF p.Pro454= (c.1362C>T) in the general population?

CARF p.Pro454= (c.1362C>T) is common (popmax 8.43%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1362C>T · rs78815956 · VCV767842

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 8.43%, afr) — too common for a highly-penetrant pathogenic allele

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 0.82	GERP -2.4, phastCons 1
Overall
CADD	11.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.43% African / African-American · 6,268/74,352 alleles

Filtering AF 8.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.18%

Overall 0.436% 6,997/1,606,110 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.43%	12
Remaining individualsnot grpmax-eligible	0.577%	173
Admixed American	0.473%	211
Middle Eastern	0.249%	402
South Asian	0.0135%	7,425
European (non-Finnish)	0.00594%	16,829

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: CARF
Protein: p.Pro454=
Coding: c.1362C>T
MANE Select: NM_024744
dbSNP: rs78815956
Type: single nucleotide variant
Location: chr2:202974364 (GRCh38)
Gene constraint: LOEUF 0.782 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.59

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

Similar variants

CARF p.Gln640Pro Uncertain significance ★★ ⚠ same type
CARF c.*377G>A Benign ★★ same type
CARF p.Pro108Ser Likely benign ★★ same type
CARF p.Thr725Ala Benign ★★ same type
CARF p.Val157Ala Likely benign ★★ same type
CARF p.Ala629Val Uncertain significance ★ ⚠ same type
CARF p.Arg142Trp Uncertain significance ★ ⚠ same type
CARF p.Arg221His 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/carf-p-pro454 (accessed [today's date]).

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