Is BBS4 p.Ile83Thr (c.248T>C) pathogenic?

BBS4 p.Ile83Thr (c.248T>C) is classified Uncertain significance in BBS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely pathogenic (0.9442); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BBS4 p.Ile83Thr (c.248T>C)?

BBS4 p.Ile83Thr (c.248T>C) is associated with Inborn genetic diseases (ClinVar).

How common is BBS4 p.Ile83Thr (c.248T>C) in the general population?

BBS4 p.Ile83Thr (c.248T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about BBS4 p.Ile83Thr (c.248T>C)?

AlphaMissense predicts likely pathogenic (score 0.9442) — an in-silico prediction, not a clinical call.

BBS4 p.Ile83Thr

c.248T>C · rs1567415169 · VCV2227410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9442 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9442	likely pathogenic
REVEL	0.516	indeterminate
SaProt	LLR -9.35	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 6.2	GERP 1.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	26.6	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 8.48e-05% European (non-Finnish) · 1/1,179,618 alleles

Overall 6.84e-05% 1/1,461,318 alleles · very rare

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: BBS4
Protein: p.Ile83Thr
Coding: c.248T>C
MANE Select: NM_033028
dbSNP: rs1567415169
Type: single nucleotide variant
Location: chr15:72715318 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB

Full BBS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BBS4 p.Ile83Ser Uncertain significance ★ ⚠ same residue
BBS4 p.Ala391Thr Uncertain significance ★★ ⚠ same condition
BBS4 p.Ala477Val Uncertain significance ★★ ⚠ same condition
BBS4 p.Asp168Asn Uncertain significance ★★ ⚠ same condition
BBS4 p.Glu355Gln Uncertain significance ★★ ⚠ same condition
BBS4 p.Ile146Thr Uncertain significance ★★ ⚠ same condition
BBS4 p.Leu148Gln Uncertain significance ★★ ⚠ same condition
BBS4 p.Leu343Ile Uncertain significance ★★ ⚠ 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/bbs4-p-ile83thr (accessed [today's date]).

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