Is BBS4 p.Met398Val (c.1192A>G) pathogenic?

BBS4 p.Met398Val (c.1192A>G) is classified Uncertain significance in BBS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.226); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BBS4 p.Met398Val (c.1192A>G)?

BBS4 p.Met398Val (c.1192A>G) is associated with Inborn genetic diseases (ClinVar).

How common is BBS4 p.Met398Val (c.1192A>G) in the general population?

BBS4 p.Met398Val (c.1192A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BBS4 p.Met398Val (c.1192A>G)?

AlphaMissense predicts likely benign (score 0.226) — an in-silico prediction, not a clinical call.

BBS4 p.Met398Val

c.1192A>G · VCV4198873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.226 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.226	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -5.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -2.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	19.54	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BBS4
Protein: p.Met398Val
Coding: c.1192A>G
MANE Select: NM_033028
Type: single nucleotide variant
Location: chr15:72735910 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 398: the 'required for localization to centrosomes' region

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.Met398Thr 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-met398val (accessed [today's date]).

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