Is AHI1 p.Arg548His (c.1643G>A) pathogenic?

AHI1 p.Arg548His (c.1643G>A) is classified Benign in AHI1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1025); Low-frequency (popmax 1.61%, nfe); Associated with Joubert syndrome 3.

What condition is associated with AHI1 p.Arg548His (c.1643G>A)?

AHI1 p.Arg548His (c.1643G>A) is associated with Joubert syndrome 3, Joubert syndrome (ClinVar).

How common is AHI1 p.Arg548His (c.1643G>A) in the general population?

AHI1 p.Arg548His (c.1643G>A) is low-frequency (popmax 1.61%, nfe) (gnomAD).

What do computational predictors say about AHI1 p.Arg548His (c.1643G>A)?

AlphaMissense predicts likely benign (score 0.1025) — an in-silico prediction, not a clinical call.

AHI1 p.Arg548His

c.1643G>A · rs35433555 · VCV128322

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1025 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.61%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1025	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Pangolin	Δ0.21	gain · loss 0.13 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 0.24	GERP -1.5, phastCons 0.008
Regional constraint	o/e 1.01	unconstrained · MANE · 202 kb · p 0.67 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.61% European (non-Finnish) · 18,711/1,161,484 alleles

Filtering AF 1.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.58%

Overall 1.36% 21,309/1,572,426 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.61%	62
Finnishnot grpmax-eligible	1.37%	73
Ashkenazi Jewishnot grpmax-eligible	1.12%	89
Remaining individualsnot grpmax-eligible	1.05%	95
Middle Eastern	0.574%	174
Admixed American	0.513%	195
South Asian	0.361%	277
African / African-American	0.229%	437
Amishnot grpmax-eligible	0.22%	454
East Asian	0.00688%	14,536

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: AHI1
Protein: p.Arg548His
Coding: c.1643G>A
MANE Select: NM_001134831
dbSNP: rs35433555
Type: single nucleotide variant
Location: chr6:135447144 (GRCh38)
Gene constraint: LOEUF 1.069 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.03 · 1 PDB
Residue 548: a UniProt-annotated variant site (in)

Full AHI1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome

Similar variants

AHI1 p.Arg548Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
AHI1 p.Arg548Leu Uncertain significance ★ ⚠ same residue
AHI1 p.Arg548= Likely benign ★ same residue
AHI1 p.Arg548Ser Uncertain significance ★ ⚠ same residue
AHI1 c.1152-1G>A Pathogenic/Likely pathogenic ★★ same condition
AHI1 c.1152-2A>G Pathogenic ★★ same condition
AHI1 c.1626+1G>A Pathogenic/Likely pathogenic ★★ same condition
AHI1 c.1779+1G>T Pathogenic/Likely 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/ahi1-p-arg548his (accessed [today's date]).

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