Is CFAP74 p.Arg280Ter (c.838C>T) pathogenic?

CFAP74 p.Arg280Ter (c.838C>T) is classified Likely pathogenic in CFAP74 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). Ultra-rare (popmax 0.0183%, amr); Associated with ciliary dyskinesia, primary, 49, without situs inversus.

What condition is associated with CFAP74 p.Arg280Ter (c.838C>T)?

CFAP74 p.Arg280Ter (c.838C>T) is associated with ciliary dyskinesia, primary, 49, without situs inversus (ClinVar).

How common is CFAP74 p.Arg280Ter (c.838C>T) in the general population?

CFAP74 p.Arg280Ter (c.838C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

How is Primary ciliary dyskinesia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CFAP74 p.Arg280Ter

c.838C>T · VCV4280102

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

ciliary dyskinesia, primary, 49, without situs inversus

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 39
Splicing
SpliceAI	Δ0.30	donor gain · deltas
Constraint at this position
Conservation	phyloP 0.18	GERP -2.2
Overall
CADD	36.0	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 0.0183% Admixed American · 11/60,008 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00521% 84/1,612,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.162%	617
Admixed Americangrpmax	0.0183%	5,455
Remaining individualsnot grpmax-eligible	0.016%	6,248
African / African-American	0.00267%	37,475
South Asian	0.0011%	91,092
European (non-Finnish)	0.00102%	98,330

Ashkenazi Jewish 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: CFAP74
Protein: p.Arg280Ter
Coding: c.838C>T
MANE Select: NM_001304360
Type: single nucleotide variant
Location: chr1:1972030 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.38

Full CFAP74 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ciliary dyskinesia, primary, 49, without situs inversus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary ciliary dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Pakistan)

Similar variants

CFAP74 p.Val768Gly Uncertain significance ★ ⚠ same condition
CFAP74 p.Arg218Trp Pathogenic ⚠ same condition
CFAP74 p.Asp1178Asn Pathogenic ⚠ same condition
CFAP74 p.Gly328Asp Pathogenic ⚠ same condition
CFAP74 p.Ser1444Thr Pathogenic ⚠ same condition
CFAP74 p.Leu975fs Likely pathogenic ★★ same condition
CFAP74 p.Phe1461fs Pathogenic/Likely pathogenic ★★ same condition
CFAP74 p.Gly570fs Likely 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/cfap74-p-arg280ter (accessed [today's date]).

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