Is RSPH9 p.Pro253Ser (c.757C>T) pathogenic?

RSPH9 p.Pro253Ser (c.757C>T) is classified Uncertain significance in RSPH9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-10-23). AlphaMissense: ambiguous (0.3488); Very rare (popmax 0.00153%, nfe); Associated with primary ciliary dyskinesia.

What condition is associated with RSPH9 p.Pro253Ser (c.757C>T)?

RSPH9 p.Pro253Ser (c.757C>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is RSPH9 p.Pro253Ser (c.757C>T) in the general population?

RSPH9 p.Pro253Ser (c.757C>T) is very rare (popmax 0.00153%, 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 RSPH9 p.Pro253Ser (c.757C>T)?

AlphaMissense predicts ambiguous (score 0.3488) — an in-silico prediction, not a clinical call.

RSPH9 p.Pro253Ser

c.757C>T · rs1449083319 · VCV1424526

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.3488	ambiguous
REVEL	0.395	indeterminate
SaProt	LLR -11.55	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 26 kb · p 0.58 · regional, not allelic
Overall
CADD	25.1	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 0.00153% European (non-Finnish) · 18/1,180,046 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00118% 19/1,614,092 alleles · very rare exomes 17/1,461,880 · genomes 2/152,212 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)grpmax	0.00153%	65,558

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro253Ser
Coding: c.757C>T
MANE Select: NM_152732
dbSNP: rs1449083319
Type: single nucleotide variant
Location: chr6:43670875 (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.Pro253= Likely benign ★ 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
RSPH9 p.Arg240Cys 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-pro253ser (accessed [today's date]).

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