Is DNAAF2 p.Pro280Ser (c.838C>T) pathogenic?

DNAAF2 p.Pro280Ser (c.838C>T) is classified Uncertain significance in DNAAF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-23). AlphaMissense: likely pathogenic (0.954); Very rare (popmax 6.85e-05%); Associated with primary ciliary dyskinesia.

What condition is associated with DNAAF2 p.Pro280Ser (c.838C>T)?

DNAAF2 p.Pro280Ser (c.838C>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAAF2 p.Pro280Ser (c.838C>T) in the general population?

DNAAF2 p.Pro280Ser (c.838C>T) is very rare (popmax 6.85e-05%) (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 DNAAF2 p.Pro280Ser (c.838C>T)?

AlphaMissense predicts likely pathogenic (score 0.954) — an in-silico prediction, not a clinical call.

DNAAF2 p.Pro280Ser

c.838C>T · rs2139582764 · VCV1394735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.954	likely pathogenic · top 3% in DNAAF2
REVEL	0.382	indeterminate
SaProt	LLR -13.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 0.68, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 9,604 bp · p 0.00019 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 6.85e-05%

Overall 6.85e-05% 1/1,459,576 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: DNAAF2
Protein: p.Pro280Ser
Coding: c.838C>T
MANE Select: NM_018139
dbSNP: rs2139582764
Type: single nucleotide variant
Location: chr14:49634312 (GRCh38)
Gene constraint: LOEUF 1.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.57

Full DNAAF2 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

DNAAF2 p.Gln504Ter Pathogenic/Likely pathogenic ★★ same condition
DNAAF2 p.Gln529Ter Pathogenic/Likely pathogenic ★★ same condition
DNAAF2 p.Glu130Ter Pathogenic/Likely pathogenic ★★ same condition
DNAAF2 p.Glu243Ter Likely pathogenic ★★ same condition
DNAAF2 p.Ala100Gly Uncertain significance ★★ ⚠ same condition
DNAAF2 p.Ala126Val Uncertain significance ★★ ⚠ same condition
DNAAF2 p.Ala211Thr Uncertain significance ★★ ⚠ same condition
DNAAF2 p.Ala358Thr 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/dnaaf2-p-pro280ser (accessed [today's date]).

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