Is RSPH3 p.Phe271Ser (c.812T>C) pathogenic?

RSPH3 p.Phe271Ser (c.812T>C) is classified Uncertain significance in RSPH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-19). AlphaMissense: likely pathogenic (0.87); Very rare (popmax 0.00133%, afr); Associated with primary ciliary dyskinesia 32.

What condition is associated with RSPH3 p.Phe271Ser (c.812T>C)?

RSPH3 p.Phe271Ser (c.812T>C) is associated with primary ciliary dyskinesia 32 (ClinVar).

How common is RSPH3 p.Phe271Ser (c.812T>C) in the general population?

RSPH3 p.Phe271Ser (c.812T>C) is very rare (popmax 0.00133%, afr) (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 RSPH3 p.Phe271Ser (c.812T>C)?

AlphaMissense predicts likely pathogenic (score 0.87) — an in-silico prediction, not a clinical call.

RSPH3 p.Phe271Ser

c.812T>C · rs141178332 · VCV2830017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.87 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

primary ciliary dyskinesia 32

Computational evidence

Protein change
AlphaMissense	0.87	likely pathogenic · top 8% in RSPH3
REVEL	0.413	indeterminate
SaProt	LLR -13.96	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 22 kb · p 0.2 · regional, not allelic
Overall
CADD	28.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F413S vs ClinVar F271S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,934 alleles

Overall 0.000657% 1/152,216 alleles · very rare

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: RSPH3
Protein: p.Phe271Ser
Coding: c.812T>C
MANE Select: NM_031924
dbSNP: rs141178332
Type: single nucleotide variant
Location: chr6:158980821 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 1 PDB

Full RSPH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia 32 — 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

RSPH3 c.205-2A>G Pathogenic ★★ same condition
RSPH3 c.859+1G>T Pathogenic/Likely pathogenic ★★ same condition
RSPH3 c.-95G>A Pathogenic ★★ same condition
RSPH3 p.Gln94Ter Likely pathogenic ★★ same condition
RSPH3 c.859+5G>A Uncertain significance ★★ same condition
RSPH3 c.-10G>T Uncertain significance ★★ ⚠ same condition
RSPH3 c.-120C>A Uncertain significance ★★ ⚠ same condition
RSPH3 c.-185G>A 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/rsph3-p-phe271ser (accessed [today's date]).

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