Is RSPH4A p.Pro445Ser (c.1333C>T) pathogenic?

RSPH4A p.Pro445Ser (c.1333C>T) is classified Uncertain significance in RSPH4A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-28). AlphaMissense: likely benign (0.3037); Very rare (popmax 0.00667%, amr); Associated with primary ciliary dyskinesia.

What condition is associated with RSPH4A p.Pro445Ser (c.1333C>T)?

RSPH4A p.Pro445Ser (c.1333C>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is RSPH4A p.Pro445Ser (c.1333C>T) in the general population?

RSPH4A p.Pro445Ser (c.1333C>T) is very rare (popmax 0.00667%, 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 RSPH4A p.Pro445Ser (c.1333C>T)?

AlphaMissense predicts likely benign (score 0.3037) — an in-silico prediction, not a clinical call.

RSPH4A p.Pro445Ser

c.1333C>T · rs146636625 · VCV843453

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3037 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.3037	likely benign
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -12.52	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 16 kb · p 0.033 · regional, not allelic
Overall
CADD	25.4	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 0.00667% Admixed American · 4/59,988 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.00384% 62/1,614,020 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,997
European (non-Finnish)	0.00475%	21,072
African / African-American	0.00267%	37,458

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: RSPH4A
Protein: p.Pro445Ser
Coding: c.1333C>T
MANE Select: NM_001010892
dbSNP: rs146636625
Type: single nucleotide variant
Location: chr6:116628040 (GRCh38)
Gene constraint: LOEUF 0.816 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.85 · 1 PDB

Full RSPH4A 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

RSPH4A p.Pro445Leu Uncertain significance ★★ ⚠ same residue
RSPH4A p.Arg465Ter Pathogenic ★★ same condition
RSPH4A p.Arg485Ter Pathogenic ★★ same condition
RSPH4A p.Arg490Ter Pathogenic/Likely pathogenic ★★ same condition
RSPH4A p.Arg520Ter Pathogenic ★★ same condition
RSPH4A p.Gln144Ter Pathogenic ★★ same condition
RSPH4A p.Gln154Ter Pathogenic ★★ same condition
RSPH4A p.Gln451Ter 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/rsph4a-p-pro445ser (accessed [today's date]).

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