Is CFAP91 p.Arg245Cys (c.733C>T) pathogenic?

CFAP91 p.Arg245Cys (c.733C>T) is classified Uncertain significance in CFAP91 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.4923); Ultra-rare (popmax 0.02%, amr).

How common is CFAP91 p.Arg245Cys (c.733C>T) in the general population?

CFAP91 p.Arg245Cys (c.733C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about CFAP91 p.Arg245Cys (c.733C>T)?

AlphaMissense predicts ambiguous (score 0.4923) — an in-silico prediction, not a clinical call.

CFAP91 p.Arg245Cys

c.733C>T · VCV4227221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4923 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Computational evidence

Protein change
AlphaMissense	0.4923	ambiguous
REVEL	0.551	indeterminate
SaProt	LLR -14.04	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 48 kb · p 0.55 · regional, not allelic
Overall
CADD	25.1	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 0.02% Admixed American · 12/59,918 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00899%

Overall 0.00347% 56/1,613,376 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.989%	101
Admixed Americangrpmax	0.02%	4,993
Middle Eastern	0.0167%	6,006
Remaining individualsnot grpmax-eligible	0.00801%	12,492
South Asian	0.0055%	18,197
Finnishnot grpmax-eligible	0.00313%	31,995
European (non-Finnish)	0.00186%	53,624

Amish 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: CFAP91
Protein: p.Arg245Cys
Coding: c.733C>T
MANE Select: NM_033364
Type: single nucleotide variant
Location: chr3:119726221 (GRCh38)
Gene constraint: LOEUF 1.129 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.20 · 1 PDB

Full CFAP91 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFAP91 p.Arg245His Uncertain significance ★ ⚠ same residue
CFAP91 c.359+1G>A Likely pathogenic ★ same type
CFAP91 p.Gln545Ter Likely pathogenic ★ same type
CFAP91 c.501-3T>C Uncertain significance ★ same type
CFAP91 p.Ala249Asp Uncertain significance ★ ⚠ same type
CFAP91 p.Ala256Thr Uncertain significance ★ ⚠ same type
CFAP91 p.Ala449Val Uncertain significance ★ ⚠ same type
CFAP91 p.Ala598Ser 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/cfap91-p-arg245cys (accessed [today's date]).

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