Is ARRB1 p.Val41Phe (c.121G>T) pathogenic?

ARRB1 p.Val41Phe (c.121G>T) is classified Uncertain significance in ARRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-10). AlphaMissense: likely pathogenic (0.9432); Very rare (popmax 0.00034%, nfe).

How common is ARRB1 p.Val41Phe (c.121G>T) in the general population?

ARRB1 p.Val41Phe (c.121G>T) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about ARRB1 p.Val41Phe (c.121G>T)?

AlphaMissense predicts likely pathogenic (score 0.9432) — an in-silico prediction, not a clinical call.

ARRB1 p.Val41Phe

c.121G>T · VCV3316136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9432	likely pathogenic
REVEL	0.33	indeterminate
SaProt	LLR -14.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.74, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 77 kb · p 1e-05 · regional, not allelic
Overall
CADD	28.0	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 0.00034% European (non-Finnish) · 4/1,175,870 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,607,984 alleles · very rare exomes 2/1,455,844 · genomes 2/152,140 · joint denominator

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: ARRB1
Protein: p.Val41Phe
Coding: c.121G>T
MANE Select: NM_004041
Type: single nucleotide variant
Location: chr11:75284271 (GRCh38)
Gene constraint: LOEUF 0.611 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 82.44 · 35 PDB
Residue 41: the 'interaction with src' region; a β-strand

Full ARRB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARRB1 p.Val41Ile Uncertain significance ★ ⚠ same residue
ARRB1 p.Ala151Thr Uncertain significance ★ ⚠ same type
ARRB1 p.Ala263Thr Uncertain significance ★ ⚠ same type
ARRB1 p.Ala82Ser Uncertain significance ★ ⚠ same type
ARRB1 p.Ala82Thr Uncertain significance ★ ⚠ same type
ARRB1 p.Arg177Ser Uncertain significance ★ ⚠ same type
ARRB1 p.Arg282Gln Uncertain significance ★ ⚠ same type
ARRB1 p.Arg312Cys Uncertain significance ★ ⚠ same type

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/arrb1-p-val41phe (accessed [today's date]).

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