Is AHI1 p.Phe746Ser (c.2237T>C) pathogenic?

AHI1 p.Phe746Ser (c.2237T>C) is classified Uncertain significance in AHI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-29). AlphaMissense: likely pathogenic (0.7739); Very rare (popmax 0.00223%, eas); Associated with Joubert syndrome.

What condition is associated with AHI1 p.Phe746Ser (c.2237T>C)?

AHI1 p.Phe746Ser (c.2237T>C) is associated with Joubert syndrome (ClinVar).

How common is AHI1 p.Phe746Ser (c.2237T>C) in the general population?

AHI1 p.Phe746Ser (c.2237T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about AHI1 p.Phe746Ser (c.2237T>C)?

AlphaMissense predicts likely pathogenic (score 0.7739) — an in-silico prediction, not a clinical call.

AHI1 p.Phe746Ser

c.2237T>C · rs1403041060 · VCV1502616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.7739	likely pathogenic
REVEL	0.569	indeterminate
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 202 kb · p 0.67 · regional, not allelic
Overall
CADD	25.9	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 0.00223% East Asian · 1/44,824 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,132 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,824
European (non-Finnish)	0.000254%	393,105

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.Phe746Ser
Coding: c.2237T>C
MANE Select: NM_001134831
dbSNP: rs1403041060
Type: single nucleotide variant
Location: chr6:135433056 (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 746: a UniProt-annotated variant site (in jbts3)

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

Disease context

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

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.2623+1G>A Pathogenic ★★ same condition
AHI1 c.2623+1G>T Pathogenic ★★ same condition
AHI1 c.3426+2T>C 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-phe746ser (accessed [today's date]).

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