Is RSPH4A p.Ala620Pro (c.1858G>C) pathogenic?

RSPH4A p.Ala620Pro (c.1858G>C) is classified Uncertain significance in RSPH4A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-29). AlphaMissense: likely pathogenic (0.9652); Absent from gnomAD v4.1; Associated with primary ciliary dyskinesia.

What condition is associated with RSPH4A p.Ala620Pro (c.1858G>C)?

RSPH4A p.Ala620Pro (c.1858G>C) is associated with primary ciliary dyskinesia (ClinVar).

How common is RSPH4A p.Ala620Pro (c.1858G>C) in the general population?

RSPH4A p.Ala620Pro (c.1858G>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.Ala620Pro (c.1858G>C)?

AlphaMissense predicts likely pathogenic (score 0.9652) — an in-silico prediction, not a clinical call.

RSPH4A p.Ala620Pro

c.1858G>C · rs1775776988 · VCV1370696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9652 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.9652	likely pathogenic · top 2% in RSPH4A
REVEL	0.508	indeterminate
SaProt	LLR -12.17	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP -0.15, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 16 kb · p 0.033 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Ala620Pro
Coding: c.1858G>C
MANE Select: NM_001010892
dbSNP: rs1775776988
Type: single nucleotide variant
Location: chr6:116630494 (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.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
RSPH4A p.Ala171Pro 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-ala620pro (accessed [today's date]).

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