Is ARB2A p.Pro209Leu (c.626C>T) pathogenic?

ARB2A p.Pro209Leu (c.626C>T) is classified Uncertain significance in ARB2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-18). AlphaMissense: likely benign (0.1215); Very rare (popmax 0.00792%, nfe).

How common is ARB2A p.Pro209Leu (c.626C>T) in the general population?

ARB2A p.Pro209Leu (c.626C>T) is very rare (popmax 0.00792%, nfe) (gnomAD).

What do computational predictors say about ARB2A p.Pro209Leu (c.626C>T)?

AlphaMissense predicts likely benign (score 0.1215) — an in-silico prediction, not a clinical call.

ARB2A p.Pro209Leu

c.626C>T · rs144174130 · VCV3235551

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1215 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00792%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1215	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -12.87	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.87, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 454 kb · p 0.66 · regional, not allelic
Overall
CADD	22.2	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 0.00792% European (non-Finnish) · 93/1,174,378 alleles

Filtering AF 0.00659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00611%

Overall 0.00599% 96/1,602,108 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00792%	12,628
Admixed American	0.0017%	58,712
Remaining individualsnot grpmax-eligible	0.00162%	61,894
South Asian	0.00113%	88,880

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: ARB2A
Protein: p.Pro209Leu
Coding: c.626C>T
MANE Select: NM_032042
dbSNP: rs144174130
Type: single nucleotide variant
Location: chr5:93881630 (GRCh38)
Structure: AlphaFold pLDDT 84.01
Residue 209: the 'disordered' region

Full ARB2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARB2A p.Pro209Ser Uncertain significance ★ ⚠ same residue
ARB2A p.Ala271Val Uncertain significance ★ ⚠ same type
ARB2A p.Ala283Val Uncertain significance ★ ⚠ same type
ARB2A p.Arg227Gly Uncertain significance ★ ⚠ same type
ARB2A p.Arg227Trp Uncertain significance ★ ⚠ same type
ARB2A p.Arg240Gln Uncertain significance ★ ⚠ same type
ARB2A p.Arg241Cys Uncertain significance ★ ⚠ same type
ARB2A p.Arg241His 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/arb2a-p-pro209leu (accessed [today's date]).

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