Is AHI1 p.Pro134Ser (c.400C>T) pathogenic?

AHI1 p.Pro134Ser (c.400C>T) is classified Conflicting classifications of pathogenicity in AHI1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0777); Ultra-rare (popmax 0.0147%, nfe); Associated with Joubert syndrome 3.

What condition is associated with AHI1 p.Pro134Ser (c.400C>T)?

AHI1 p.Pro134Ser (c.400C>T) is associated with Joubert syndrome 3, Joubert syndrome (ClinVar).

How common is AHI1 p.Pro134Ser (c.400C>T) in the general population?

AHI1 p.Pro134Ser (c.400C>T) is ultra-rare (popmax 0.0147%, nfe) (gnomAD).

What do computational predictors say about AHI1 p.Pro134Ser (c.400C>T)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

AHI1 p.Pro134Ser

c.400C>T · rs368077581 · VCV391535

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 3

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.008	strongly benign-leaning
SaProt	LLR -5.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.38	GERP -3.1
Regional constraint	o/e 1.01	unconstrained · MANE · 202 kb · p 0.67 · regional, not allelic
Overall
CADD	0.187	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 0.0147% European (non-Finnish) · 173/1,179,856 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0122%

Overall 0.0113% 183/1,613,714 alleles · ultra-rare exomes 169/1,461,626 · genomes 14/152,088 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0147%	6,820
Remaining individualsnot grpmax-eligible	0.00961%	10,411
Admixed American	0.00334%	29,983
Finnishnot grpmax-eligible	0.00156%	63,998
South Asian	0.0011%	91,074

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.Pro134Ser
Coding: c.400C>T
MANE Select: NM_001134831
dbSNP: rs368077581
Type: single nucleotide variant
Location: chr6:135466163 (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 134: the 'disordered' region

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.Pro134Thr 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
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-pro134ser (accessed [today's date]).

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