Is RSPH3 p.Arg235His (c.704G>A) pathogenic?

RSPH3 p.Arg235His (c.704G>A) is classified Uncertain significance in RSPH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). AlphaMissense: ambiguous (0.4479); Very rare (popmax 0.00439%, sas); Associated with Inborn genetic diseases.

What condition is associated with RSPH3 p.Arg235His (c.704G>A)?

RSPH3 p.Arg235His (c.704G>A) is associated with Inborn genetic diseases, primary ciliary dyskinesia 32 (ClinVar).

How common is RSPH3 p.Arg235His (c.704G>A) in the general population?

RSPH3 p.Arg235His (c.704G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about RSPH3 p.Arg235His (c.704G>A)?

AlphaMissense predicts ambiguous (score 0.4479) — an in-silico prediction, not a clinical call.

RSPH3 p.Arg235His

c.704G>A · rs758822234 · VCV856045

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4479	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -11.14	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 22 kb · p 0.2 · regional, not allelic
Overall
CADD	29.0	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 R377H vs ClinVar R235H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,082 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00198% 32/1,613,800 alleles · very rare exomes 29/1,461,726 · genomes 3/152,074 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
African / African-American	0.00267%	37,432
East Asian	0.00223%	44,886
European (non-Finnish)	0.00203%	49,162
Remaining individualsnot grpmax-eligible	0.0016%	62,474

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.Arg235His
Coding: c.704G>A
MANE Select: NM_031924
dbSNP: rs758822234
Type: single nucleotide variant
Location: chr6:158980929 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: primary ciliary dyskinesia 32

Similar variants

RSPH3 p.Arg235Cys 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
RSPH3 c.-120C>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-arg235his (accessed [today's date]).

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