Is BBS4 p.Gln155Pro (c.464A>C) pathogenic?

BBS4 p.Gln155Pro (c.464A>C) is classified Uncertain significance in BBS4 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-09-19). AlphaMissense: likely pathogenic (0.7708); Very rare (popmax 0.000932%, nfe); Associated with BBS4-related disorder.

What condition is associated with BBS4 p.Gln155Pro (c.464A>C)?

BBS4 p.Gln155Pro (c.464A>C) is associated with BBS4-related disorder, inherited retinal dystrophy (ClinVar).

How common is BBS4 p.Gln155Pro (c.464A>C) in the general population?

BBS4 p.Gln155Pro (c.464A>C) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about BBS4 p.Gln155Pro (c.464A>C)?

AlphaMissense predicts likely pathogenic (score 0.7708) — an in-silico prediction, not a clinical call.

BBS4 p.Gln155Pro

c.464A>C · rs2065632499 · VCV2636498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7708 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BBS4-related disorder

Computational evidence

Protein change
AlphaMissense	0.7708	likely pathogenic
REVEL	0.161	moderately benign-leaning
SaProt	LLR -11.76	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	23.6	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 0.000932% European (non-Finnish) · 11/1,179,918 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,613,904 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.Gln155Pro
Coding: c.464A>C
MANE Select: NM_033028
dbSNP: rs2065632499
Type: single nucleotide variant
Location: chr15:72724532 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 155: the 'interaction with pcm1' region

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

Disease context

BBS4-related disorder

Also linked: inherited retinal dystrophy

Similar variants

BBS4 p.Gln155Ter Likely pathogenic ★ same residue
BBS4 p.Gln155Lys Uncertain significance ★ ⚠ same residue
BBS4 p.Gln155= Likely benign ★ same residue
BBS4 c.1248+2T>C Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.157-3C>G Pathogenic ★★ same condition
BBS4 c.220+1G>C Pathogenic ★★ same condition
BBS4 c.24+1G>A Likely pathogenic ★★ same condition
BBS4 c.332+8T>C Pathogenic/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/bbs4-p-gln155pro (accessed [today's date]).

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