Is BBS2 p.Arg374Trp (c.1120C>T) pathogenic?

BBS2 p.Arg374Trp (c.1120C>T) is classified Uncertain significance in BBS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-10-01). AlphaMissense: likely benign (0.119); Very rare (popmax 0.00668%, eas); Associated with inherited retinal dystrophy.

What condition is associated with BBS2 p.Arg374Trp (c.1120C>T)?

BBS2 p.Arg374Trp (c.1120C>T) is associated with inherited retinal dystrophy, Bardet-Biedl syndrome 2, retinitis pigmentosa 74 (ClinVar).

How common is BBS2 p.Arg374Trp (c.1120C>T) in the general population?

BBS2 p.Arg374Trp (c.1120C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about BBS2 p.Arg374Trp (c.1120C>T)?

AlphaMissense predicts likely benign (score 0.119) — an in-silico prediction, not a clinical call.

BBS2 p.Arg374Trp

c.1120C>T · rs143607562 · VCV949257

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.119	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -10.26	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.20	acceptor loss · deltas
Pangolin	Δ0.38	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.6	GERP -1.5, phastCons 0.89
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	18.0	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 0.00668% East Asian · 3/44,898 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00462%

Overall 0.00514% 83/1,613,934 alleles · very rare exomes 79/1,461,882 · genomes 4/152,052 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,966
European (non-Finnish)	0.00619%	16,164
African / African-American	0.00534%	18,720
Remaining individualsnot grpmax-eligible	0.0032%	31,241
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: BBS2
Protein: p.Arg374Trp
Coding: c.1120C>T
MANE Select: NM_031885
dbSNP: rs143607562
Type: single nucleotide variant
Location: chr16:56501458 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49

Full BBS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome 2 retinitis pigmentosa 74 Bardet-Biedl syndrome

Similar variants

BBS2 p.Arg374Gln Uncertain significance ★★ ⚠ same residue
BBS2 c.118-1G>T Likely pathogenic ★★ same condition
BBS2 c.118-2A>C Likely pathogenic ★★ same condition
BBS2 c.118-2A>G Likely pathogenic ★★ same condition
BBS2 c.1225+2T>C Likely pathogenic ★★ same condition
BBS2 c.1225+2T>G Likely pathogenic ★★ same condition
BBS2 c.1397+1G>A Pathogenic/Likely pathogenic ★★ same condition
BBS2 c.1397+2T>C 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/bbs2-p-arg374trp (accessed [today's date]).

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