Is RSPH3 p.His331Arg (c.992A>G) pathogenic?

RSPH3 p.His331Arg (c.992A>G) is classified Conflicting classifications of pathogenicity in RSPH3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-03-04). AlphaMissense: likely benign (0.0558); Rare (popmax 0.222%, sas); Associated with primary ciliary dyskinesia 32.

What condition is associated with RSPH3 p.His331Arg (c.992A>G)?

RSPH3 p.His331Arg (c.992A>G) is associated with primary ciliary dyskinesia 32 (ClinVar).

How common is RSPH3 p.His331Arg (c.992A>G) in the general population?

RSPH3 p.His331Arg (c.992A>G) is rare (popmax 0.222%, sas) (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.His331Arg (c.992A>G)?

AlphaMissense predicts likely benign (score 0.0558) — an in-silico prediction, not a clinical call.

RSPH3 p.His331Arg

c.992A>G · rs78116655 · VCV800220

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0558 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.222%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 32

Computational evidence

Protein change
AlphaMissense	0.0558	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -5.29	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 -7.3	GERP -9.1
Regional constraint	o/e 0.94	unconstrained · MANE · 22 kb · p 0.2 · regional, not allelic
Overall
CADD	0.001	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM H473R vs ClinVar H331R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.222% South Asian · 202/91,076 alleles

Filtering AF 0.197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.187%

Overall 0.0129% 209/1,614,156 alleles · rare exomes 198/1,461,824 · genomes 11/152,332 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.222%	451
Remaining individualsnot grpmax-eligible	0.0032%	31,254
African / African-American	0.00266%	37,526
European (non-Finnish)	0.000254%	393,343

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.His331Arg
Coding: c.992A>G
MANE Select: NM_031924
dbSNP: rs78116655
Type: single nucleotide variant
Location: chr6:158977803 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 1 PDB
Residue 473 UniProt numbering: the 'disordered' region

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 p.His331Pro Benign/Likely benign ★★ same residue
RSPH3 p.His331Leu Uncertain significance ★ ⚠ same residue
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

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-his331arg (accessed [today's date]).

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