Is BBS5 p.Val127Ala (c.380T>C) pathogenic?

BBS5 p.Val127Ala (c.380T>C) is classified Uncertain significance in BBS5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-03). AlphaMissense: likely pathogenic (0.679); Very rare (popmax 0.00333%, amr); Associated with BBS5-related disorder.

What condition is associated with BBS5 p.Val127Ala (c.380T>C)?

BBS5 p.Val127Ala (c.380T>C) is associated with BBS5-related disorder (ClinVar).

How common is BBS5 p.Val127Ala (c.380T>C) in the general population?

BBS5 p.Val127Ala (c.380T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about BBS5 p.Val127Ala (c.380T>C)?

AlphaMissense predicts likely pathogenic (score 0.679) — an in-silico prediction, not a clinical call.

BBS5 p.Val127Ala

c.380T>C · VCV3354037

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.679 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BBS5-related disorder

Computational evidence

Protein change
AlphaMissense	0.679	likely pathogenic
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -11.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.023 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00333% Admixed American · 2/60,020 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000205% 3/1,460,668 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,010
Remaining individualsnot grpmax-eligible	0.0016%	62,464

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: BBS5
Protein: p.Val127Ala
Coding: c.380T>C
MANE Select: NM_152384
Type: single nucleotide variant
Location: chr2:169488108 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.87 · 1 PDB

Full BBS5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BBS5-related disorder

Similar variants

BBS5 p.Val127= Likely benign ★ same residue
BBS5 c.209-2A>G Likely pathogenic ★★ same condition
BBS5 c.522+3A>G Pathogenic/Likely pathogenic ★★ same condition
BBS5 p.Arg138His Pathogenic/Likely pathogenic ★★ same condition
BBS5 p.Gln205Ter Likely pathogenic ★★ same condition
BBS5 p.Gln20Ter Pathogenic/Likely pathogenic ★★ same condition
BBS5 p.Gly72Ser Pathogenic/Likely pathogenic ★★ same condition
BBS5 p.Met1Thr 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/bbs5-p-val127ala (accessed [today's date]).

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