Is RSPH4A p.Pro606Arg (c.1817C>G) pathogenic?

RSPH4A p.Pro606Arg (c.1817C>G) is classified Uncertain significance in RSPH4A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). AlphaMissense: ambiguous (0.411); Ultra-rare (popmax 0.0156%, eas); Associated with primary ciliary dyskinesia.

What condition is associated with RSPH4A p.Pro606Arg (c.1817C>G)?

RSPH4A p.Pro606Arg (c.1817C>G) is associated with primary ciliary dyskinesia (ClinVar).

How common is RSPH4A p.Pro606Arg (c.1817C>G) in the general population?

RSPH4A p.Pro606Arg (c.1817C>G) is ultra-rare (popmax 0.0156%, eas) (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.Pro606Arg (c.1817C>G)?

AlphaMissense predicts ambiguous (score 0.411) — an in-silico prediction, not a clinical call.

RSPH4A p.Pro606Arg

c.1817C>G · rs138413282 · VCV977550

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.411 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.411	ambiguous
REVEL	0.301	indeterminate
SaProt	LLR -12.23	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 0.99
Regional constraint	o/e 0.93	unconstrained · MANE · 16 kb · p 0.033 · regional, not allelic
Overall
CADD	23.7	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 0.0156% East Asian · 7/44,748 alleles

Filtering AF 0.00728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00516%

Overall 0.00313% 50/1,594,908 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,393
African / African-American	0.0107%	9,305
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,466
European (non-Finnish)	0.00284%	35,238
Remaining individualsnot grpmax-eligible	0.00162%	61,812

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.Pro606Arg
Coding: c.1817C>G
MANE Select: NM_001010892
dbSNP: rs138413282
Type: single nucleotide variant
Location: chr6:116630453 (GRCh38)
Gene constraint: LOEUF 0.816 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.85 · 1 PDB

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.Pro606Leu Uncertain significance ★★ ⚠ 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
RSPH4A p.Gln451Ter 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-pro606arg (accessed [today's date]).

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