Is ARRB2 p.Ser13Leu (c.38C>T) pathogenic?

ARRB2 p.Ser13Leu (c.38C>T) is classified Uncertain significance in ARRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-15). AlphaMissense: likely pathogenic (0.9201); Very rare (popmax 0.00171%, amr).

How common is ARRB2 p.Ser13Leu (c.38C>T) in the general population?

ARRB2 p.Ser13Leu (c.38C>T) is very rare (popmax 0.00171%, amr) (gnomAD).

What do computational predictors say about ARRB2 p.Ser13Leu (c.38C>T)?

AlphaMissense predicts likely pathogenic (score 0.9201) — an in-silico prediction, not a clinical call.

ARRB2 p.Ser13Leu

c.38C>T · rs745795485 · VCV2335097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9201	likely pathogenic
REVEL	0.146	moderately benign-leaning
SaProt	LLR -11.65	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 10 kb · p 5.2e-12 · regional, not allelic
Overall
CADD	31.0	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 0.00171% Admixed American · 1/58,562 alleles

Filtering AF 0.000544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00043%

Overall 0.000997% 16/1,605,004 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00171%	58,562
Remaining individualsnot grpmax-eligible	0.00161%	62,238
African / African-American	0.00134%	74,870
South Asian	0.00112%	89,258
European (non-Finnish)	0.00102%	97,968

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: ARRB2
Protein: p.Ser13Leu
Coding: c.38C>T
MANE Select: NM_004313
dbSNP: rs745795485
Type: single nucleotide variant
Location: chr17:4715027 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 83.97 · 1 PDB

Full ARRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARRB2 p.Ile82= Benign ★★ same type
ARRB2 p.Leu288= Benign ★★ same type
ARRB2 p.Ala362Thr Uncertain significance ★ ⚠ same type
ARRB2 p.Arg100Cys Uncertain significance ★ ⚠ same type
ARRB2 p.Arg148Gln Uncertain significance ★ ⚠ same type
ARRB2 p.Arg189Cys Uncertain significance ★ ⚠ same type
ARRB2 p.Arg196Gln Uncertain significance ★ ⚠ same type
ARRB2 p.Arg26Gln 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/arrb2-p-ser13leu (accessed [today's date]).

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