Is DNAAF3 p.Pro45Ser (c.133C>T) pathogenic?

DNAAF3 p.Pro45Ser (c.133C>T) is classified Conflicting classifications of pathogenicity in DNAAF3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-30). AlphaMissense: likely benign (0.1154); Ultra-rare (popmax 0.0977%, sas); Associated with primary ciliary dyskinesia.

What condition is associated with DNAAF3 p.Pro45Ser (c.133C>T)?

DNAAF3 p.Pro45Ser (c.133C>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAAF3 p.Pro45Ser (c.133C>T) in the general population?

DNAAF3 p.Pro45Ser (c.133C>T) is ultra-rare (popmax 0.0977%, sas) (gnomAD).

How is Primary ciliary dyskinesia inherited?

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

What do computational predictors say about DNAAF3 p.Pro45Ser (c.133C>T)?

AlphaMissense predicts likely benign (score 0.1154) — an in-silico prediction, not a clinical call.

DNAAF3 p.Pro45Ser

c.133C>T · VCV3714773

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1154 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0977%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.1154	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -5.24	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 3.6	GERP 0.041, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,348 bp · p 0.5 · regional, not allelic
Overall
CADD	16.47	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 0.0977% South Asian · 89/91,096 alleles

Filtering AF 0.0812% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0752%

Overall 0.0062% 100/1,614,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0977%	1,024
Middle Eastern	0.0164%	6,084
Admixed American	0.0117%	8,572
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000169%	590,026

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: DNAAF3
Protein: p.Pro45Ser
Coding: c.133C>T
MANE Select: NM_001256715
Type: single nucleotide variant
Location: chr19:55165953 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.06

Full DNAAF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia — 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

DNAAF3 p.Pro45Arg Uncertain significance ★★ ⚠ same residue
DNAAF3 p.Pro45Leu Uncertain significance ★ ⚠ same residue
DNAAF3 c.789+1G>C Likely pathogenic ★★ same condition
DNAAF3 p.Asn252Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
DNAAF3 p.Gln301Ter Pathogenic/Likely pathogenic ★★ same condition
DNAAF3 c.789+5G>C Uncertain significance ★★ same condition
DNAAF3 c.-37G>A Uncertain significance ★★ same condition
DNAAF3 p.Ala128Thr Uncertain significance ★★ ⚠ 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/dnaaf3-p-pro45ser (accessed [today's date]).

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