Is RSPH9 p.Ser9Pro (c.25T>C) pathogenic?

RSPH9 p.Ser9Pro (c.25T>C) is classified Uncertain significance in RSPH9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.6696); Very rare (popmax 0.00333%, amr); Associated with primary ciliary dyskinesia.

What condition is associated with RSPH9 p.Ser9Pro (c.25T>C)?

RSPH9 p.Ser9Pro (c.25T>C) is associated with primary ciliary dyskinesia (ClinVar).

How common is RSPH9 p.Ser9Pro (c.25T>C) in the general population?

RSPH9 p.Ser9Pro (c.25T>C) 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 RSPH9 p.Ser9Pro (c.25T>C)?

AlphaMissense predicts likely pathogenic (score 0.6696) — an in-silico prediction, not a clinical call.

RSPH9 p.Ser9Pro

c.25T>C · rs767450427 · VCV1023203

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6696 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.6696	likely pathogenic
REVEL	0.16	moderately benign-leaning
SaProt	LLR -10.45	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.54, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 26 kb · p 0.58 · regional, not allelic
Overall
CADD	23.4	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 0.00333% Admixed American · 2/59,996 alleles

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

Overall 0.000186% 3/1,612,696 alleles · very rare exomes 2/1,460,488 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,998
African / African-American	0.00133%	74,942

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: RSPH9
Protein: p.Ser9Pro
Coding: c.25T>C
MANE Select: NM_152732
dbSNP: rs767450427
Type: single nucleotide variant
Location: chr6:43645123 (GRCh38)
Gene constraint: LOEUF 1.316 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.03 · 1 PDB

Full RSPH9 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

RSPH9 p.Ser9= Likely benign ★ same residue
RSPH9 p.Ser9Ala Uncertain significance ★ same residue
RSPH9 p.Arg156Ter Pathogenic ★★ same condition
RSPH9 p.Tyr39Ter Pathogenic ★★ same condition
RSPH9 p.Ala150Val Uncertain significance ★★ ⚠ same condition
RSPH9 p.Ala94Val Uncertain significance ★★ ⚠ same condition
RSPH9 p.Arg139Cys Uncertain significance ★★ ⚠ same condition
RSPH9 p.Arg139His 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/rsph9-p-ser9pro (accessed [today's date]).

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