Is AHI1 p.Ser528Ter (c.1583C>A) pathogenic?

AHI1 p.Ser528Ter (c.1583C>A) is classified Pathogenic/Likely pathogenic in AHI1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-28). Very rare (popmax 8.49e-05%, nfe); Associated with Joubert syndrome 3.

What condition is associated with AHI1 p.Ser528Ter (c.1583C>A)?

AHI1 p.Ser528Ter (c.1583C>A) is associated with Joubert syndrome 3, Joubert syndrome (ClinVar).

How common is AHI1 p.Ser528Ter (c.1583C>A) in the general population?

AHI1 p.Ser528Ter (c.1583C>A) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

AHI1 p.Ser528Ter

c.1583C>A · rs2128058828 · VCV1070164

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

Joubert syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 29
REVEL	0.536	indeterminate
Splicing
SpliceAI	Δ0.27	donor loss, 43 bp away · masked 0 · deltas
Pangolin	Δ0.40	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Overall
CADD	40.0	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 8.49e-05% European (non-Finnish) · 1/1,178,144 alleles

Overall 6.21e-05% 1/1,611,138 alleles · very rare exomes 1/1,458,884 · genomes 0/152,254 · joint denominator

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.Ser528Ter
Coding: c.1583C>A
MANE Select: NM_001134831
dbSNP: rs2128058828
Type: single nucleotide variant
Location: chr6:135448333 (GRCh38)
Gene constraint: LOEUF 1.069 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.03 · 1 PDB

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 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
AHI1 c.2492+1G>A Pathogenic/Likely pathogenic ★★ same condition
AHI1 c.2493-2A>G Pathogenic/Likely pathogenic ★★ same condition
AHI1 c.2623+1G>A Pathogenic ★★ same condition
AHI1 c.2623+1G>T 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-ser528ter (accessed [today's date]).

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