Is AHI1 p.Ser221Ter (c.662C>G) pathogenic?

AHI1 p.Ser221Ter (c.662C>G) is classified Pathogenic in AHI1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-04-17). Very rare (popmax 0.00077%, nfe); Associated with AHI1-related disorder.

What condition is associated with AHI1 p.Ser221Ter (c.662C>G)?

AHI1 p.Ser221Ter (c.662C>G) is associated with AHI1-related disorder, Joubert syndrome 3, Joubert syndrome and related disorders (ClinVar).

How common is AHI1 p.Ser221Ter (c.662C>G) in the general population?

AHI1 p.Ser221Ter (c.662C>G) is very rare (popmax 0.00077%, nfe) (gnomAD).

AHI1 p.Ser221Ter

c.662C>G · rs863225138 · VCV217538

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00077%, nfe)

Conditions

AHI1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 29
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Overall
CADD	35.0	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 0.00077% European (non-Finnish) · 9/1,168,952 alleles

Filtering AF 0.000362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000262%

Overall 0.000567% 9/1,588,256 alleles · very rare exomes 6/1,436,162 · genomes 3/152,094 · 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.Ser221Ter
Coding: c.662C>G
MANE Select: NM_001134831
dbSNP: rs863225138
Type: single nucleotide variant
Location: chr6:135465901 (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 221: the 'interaction with hap1' region; the 'disordered' region

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

Disease context

AHI1-related disorder

Also linked: Joubert syndrome 3 Joubert syndrome and related disorders Joubert syndrome

Similar variants

AHI1 p.Ser221= Likely benign ★ 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
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

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-ser221ter (accessed [today's date]).

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