Is RSPH4A p.Pro87Ser (c.259C>T) pathogenic?

RSPH4A p.Pro87Ser (c.259C>T) is classified Uncertain significance in RSPH4A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-15). AlphaMissense: likely benign (0.0693); Ultra-rare (popmax 0.0165%, sas); Associated with primary ciliary dyskinesia.

What condition is associated with RSPH4A p.Pro87Ser (c.259C>T)?

RSPH4A p.Pro87Ser (c.259C>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is RSPH4A p.Pro87Ser (c.259C>T) in the general population?

RSPH4A p.Pro87Ser (c.259C>T) is ultra-rare (popmax 0.0165%, 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 RSPH4A p.Pro87Ser (c.259C>T)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

RSPH4A p.Pro87Ser

c.259C>T · rs767490154 · VCV238209

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.025	GERP -2.5
Regional constraint	o/e 0.93	unconstrained · MANE · 16 kb · p 0.033 · regional, not allelic
Overall
CADD	7.698	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 0.0165% South Asian · 15/91,080 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00109% 16/1,461,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,072
European (non-Finnish)	8.47e-05%	1,180,040

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.Pro87Ser
Coding: c.259C>T
MANE Select: NM_001010892
dbSNP: rs767490154
Type: single nucleotide variant
Location: chr6:116616882 (GRCh38)
Gene constraint: LOEUF 0.816 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.85 · 1 PDB
Residue 87: the 'disordered' region; a UniProt-annotated variant site (in cild11)

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.Pro87Leu Uncertain significance ★ ⚠ same residue
RSPH4A p.Pro87= Likely benign ★ 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

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-pro87ser (accessed [today's date]).

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