Is CARF p.Pro108Ser (c.322C>T) pathogenic?

CARF p.Pro108Ser (c.322C>T) is classified Likely benign in CARF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-01). AlphaMissense: likely benign (0.0705); Rare (popmax 0.812%, nfe).

How common is CARF p.Pro108Ser (c.322C>T) in the general population?

CARF p.Pro108Ser (c.322C>T) is rare (popmax 0.812%, nfe) (gnomAD).

What do computational predictors say about CARF p.Pro108Ser (c.322C>T)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

CARF p.Pro108Ser

c.322C>T · rs115268453 · VCV784583

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.812%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -6.91	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 0.77	GERP 0.14, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 42 kb · p 0.0037 · regional, not allelic
Overall
CADD	15.19	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 0.812% European (non-Finnish) · 9,579/1,179,632 alleles

Filtering AF 0.798% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.793%

Overall 0.64% 10,323/1,612,966 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.812%	123
Remaining individualsnot grpmax-eligible	0.5%	200
Ashkenazi Jewishnot grpmax-eligible	0.298%	336
Admixed American	0.292%	342
African / African-American	0.124%	804
Finnishnot grpmax-eligible	0.0815%	1,227
Middle Eastern	0.033%	3,029
South Asian	0.0242%	4,136

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.Pro108Ser
Coding: c.322C>T
MANE Select: NM_024744
dbSNP: rs115268453
Type: single nucleotide variant
Location: chr2:202952574 (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.Pro108Leu Uncertain significance ★ ⚠ same residue
CARF p.Gln640Pro Uncertain significance ★★ ⚠ same type
CARF c.*377G>A Benign ★★ same type
CARF p.Pro454= 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

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-pro108ser (accessed [today's date]).

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