Is DNAAF3 p.Pro506Ser (c.1516C>T) pathogenic?

DNAAF3 p.Pro506Ser (c.1516C>T) is classified Uncertain significance in DNAAF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.0669); Very rare (popmax 0.00333%, amr); Associated with primary ciliary dyskinesia.

What condition is associated with DNAAF3 p.Pro506Ser (c.1516C>T)?

DNAAF3 p.Pro506Ser (c.1516C>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAAF3 p.Pro506Ser (c.1516C>T) in the general population?

DNAAF3 p.Pro506Ser (c.1516C>T) is very rare (popmax 0.00333%, amr) (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.Pro506Ser (c.1516C>T)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

DNAAF3 p.Pro506Ser

c.1516C>T · rs2085770745 · VCV2244639

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -5.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.47	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -0.22	GERP -2.4
Regional constraint	o/e 1.02	unconstrained · MANE · 7,348 bp · p 0.5 · regional, not allelic
Overall
CADD	6.115	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,998 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,760 alleles · very rare

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.Pro506Ser
Coding: c.1516C>T
MANE Select: NM_001256715
dbSNP: rs2085770745
Type: single nucleotide variant
Location: chr19:55159172 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.06
Residue 506: the 'disordered' region

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 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
DNAAF3 p.Ala256Gly Uncertain significance ★★ ⚠ same condition
DNAAF3 p.Ala284Asp 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-pro506ser (accessed [today's date]).

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