Is RSPH9 p.Phe249Ser (c.746T>C) pathogenic?

RSPH9 p.Phe249Ser (c.746T>C) is classified Likely benign in RSPH9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-19). AlphaMissense: likely pathogenic (0.5791); Rare (popmax 0.164%, sas); Associated with primary ciliary dyskinesia.

What condition is associated with RSPH9 p.Phe249Ser (c.746T>C)?

RSPH9 p.Phe249Ser (c.746T>C) is associated with primary ciliary dyskinesia (ClinVar).

How common is RSPH9 p.Phe249Ser (c.746T>C) in the general population?

RSPH9 p.Phe249Ser (c.746T>C) is rare (popmax 0.164%, sas) (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.Phe249Ser (c.746T>C)?

AlphaMissense predicts likely pathogenic (score 0.5791) — an in-silico prediction, not a clinical call.

RSPH9 p.Phe249Ser

c.746T>C · rs570578504 · VCV2528109

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5791 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.164%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.5791	likely pathogenic
REVEL	0.519	indeterminate
SaProt	LLR -10.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 26 kb · p 0.58 · regional, not allelic
Overall
CADD	26.5	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 0.164% South Asian · 149/91,082 alleles

Filtering AF 0.142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.134%

Overall 0.00954% 154/1,614,226 alleles · rare exomes 147/1,461,886 · genomes 7/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.164%	611
Remaining individualsnot grpmax-eligible	0.008%	12,502

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.Phe249Ser
Coding: c.746T>C
MANE Select: NM_152732
dbSNP: rs570578504
Type: single nucleotide variant
Location: chr6:43670864 (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.Phe249Ile Likely benign ★ same residue
RSPH9 p.Phe249Thr 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

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-phe249ser (accessed [today's date]).

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