Is RSPH4A p.Ser35Pro (c.103T>C) pathogenic?

RSPH4A p.Ser35Pro (c.103T>C) is classified Uncertain significance in RSPH4A (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0505); Absent from gnomAD v4.1; Associated with primary ciliary dyskinesia 11.

What condition is associated with RSPH4A p.Ser35Pro (c.103T>C)?

RSPH4A p.Ser35Pro (c.103T>C) is associated with primary ciliary dyskinesia 11 (ClinVar).

How common is RSPH4A p.Ser35Pro (c.103T>C) in the general population?

RSPH4A p.Ser35Pro (c.103T>C) is absent from gnomAD v4.1 (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.Ser35Pro (c.103T>C)?

AlphaMissense predicts likely benign (score 0.0505) — an in-silico prediction, not a clinical call.

RSPH4A p.Ser35Pro

c.103T>C · rs2482776933 · VCV3236432

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0505 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 11

Computational evidence

Protein change
AlphaMissense	0.0505	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -5.40	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 0.32	GERP -0.3
Regional constraint	o/e 0.93	unconstrained · MANE · 16 kb · p 0.033 · regional, not allelic
Overall
CADD	6.286	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RSPH4A
Protein: p.Ser35Pro
Coding: c.103T>C
MANE Select: NM_001010892
dbSNP: rs2482776933
Type: single nucleotide variant
Location: chr6:116616726 (GRCh38)
Gene constraint: LOEUF 0.816 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.85 · 1 PDB
Residue 35: the 'disordered' region

Full RSPH4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia 11 — 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.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
RSPH4A p.Ala196Thr Uncertain significance ★★ ⚠ same condition
RSPH4A p.Ala416Val 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/rsph4a-p-ser35pro (accessed [today's date]).

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