Is RSPH4A p.Ser671fs (c.2010dup) pathogenic?

RSPH4A p.Ser671fs (c.2010dup) is classified Likely pathogenic in RSPH4A (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-06). Very rare (popmax 0.00446%, eas); Associated with primary ciliary dyskinesia.

What condition is associated with RSPH4A p.Ser671fs (c.2010dup)?

RSPH4A p.Ser671fs (c.2010dup) is associated with primary ciliary dyskinesia (ClinVar).

How common is RSPH4A p.Ser671fs (c.2010dup) in the general population?

RSPH4A p.Ser671fs (c.2010dup) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Primary ciliary dyskinesia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

RSPH4A p.Ser671fs

c.2010dup · rs1400425886 · VCV642424

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,613,348 alleles · very rare exomes 4/1,461,250 · genomes 1/152,098 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,439
Admixed American	0.00333%	29,991
European (non-Finnish)	8.47e-05%	1,179,966

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.Ser671fs
Coding: c.2010dup
MANE Select: NM_001010892
dbSNP: rs1400425886
Type: Duplication
Location: chr6:116632296 (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.Ser671Gly Uncertain significance ★ ⚠ same residue
RSPH4A p.Ser498fs Pathogenic/Likely pathogenic ★★ same condition
RSPH4A p.Glu175fs Pathogenic ★ same condition
RSPH4A p.Thr69fs Pathogenic ★ same condition
RSPH4A p.Trp607fs Likely pathogenic ★ same condition
RSPH4A c.1916+2dup Uncertain significance ★ same condition
RSPH4A c.1662+2_1662+5del Pathogenic/Likely pathogenic ★★ same condition
RSPH4A c.921+3_921+6del 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-ser671fs (accessed [today's date]).

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