Is DNAAF4 p.Pro2Ser (c.4C>T) pathogenic?

DNAAF4 p.Pro2Ser (c.4C>T) is classified Uncertain significance in DNAAF4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-09-01). AlphaMissense: likely benign (0.2927); Rare (popmax 0.15%, nfe); Associated with primary ciliary dyskinesia 25.

What condition is associated with DNAAF4 p.Pro2Ser (c.4C>T)?

DNAAF4 p.Pro2Ser (c.4C>T) is associated with primary ciliary dyskinesia 25, dyslexia, susceptibility to, 1, primary ciliary dyskinesia (ClinVar).

How common is DNAAF4 p.Pro2Ser (c.4C>T) in the general population?

DNAAF4 p.Pro2Ser (c.4C>T) is rare (popmax 0.15%, nfe) (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 DNAAF4 p.Pro2Ser (c.4C>T)?

AlphaMissense predicts likely benign (score 0.2927) — an in-silico prediction, not a clinical call.

DNAAF4 p.Pro2Ser

c.4C>T · rs143493699 · VCV578519

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2927 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.15%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 25

Computational evidence

Protein change
AlphaMissense	0.2927	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.47	acceptor gain · deltas
Pangolin	Δ0.38	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.7	GERP 2.6, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 68 kb · p 7.4e-05 · regional, not allelic
Overall
CADD	25.1	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 0.15% European (non-Finnish) · 1,756/1,172,602 alleles

Filtering AF 0.144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.142%

Overall 0.119% 1,905/1,601,526 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.15%	668
Remaining individualsnot grpmax-eligible	0.123%	816
Finnishnot grpmax-eligible	0.0532%	1,881
Admixed American	0.0342%	2,925
African / African-American	0.0242%	4,136
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,360

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: DNAAF4
Protein: p.Pro2Ser
Coding: c.4C>T
MANE Select: NM_130810
dbSNP: rs143493699
Type: single nucleotide variant
Location: chr15:55498326 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.00
Residue 2: a UniProt-annotated variant site (in)

Full DNAAF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia 25 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyslexia, susceptibility to, 1 primary ciliary dyskinesia

For Primary ciliary dyskinesia (Orphanet):

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

Similar variants

DNAAF4 p.Pro2Leu Uncertain significance ★ ⚠ same residue
DNAAF4 p.Pro2Thr Uncertain significance ★ ⚠ same residue
DNAAF4 c.1153+1G>A Pathogenic ★★ same condition
DNAAF4 p.Arg270Ter Pathogenic/Likely pathogenic ★★ same condition
DNAAF4 p.Arg330Trp Pathogenic/Likely pathogenic ★★ same condition
DNAAF4 p.Arg371Ter Pathogenic/Likely pathogenic ★★ same condition
DNAAF4 p.Glu109Ter Pathogenic ★★ same condition
DNAAF4 p.Arg152Trp 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/dnaaf4-p-pro2ser (accessed [today's date]).

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