Is ARAF p.Pro200Arg (c.599C>G) pathogenic?

ARAF p.Pro200Arg (c.599C>G) is classified Uncertain significance in ARAF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-15). AlphaMissense: likely benign (0.1149); Ultra-rare (popmax 0.0136%, nfe).

How common is ARAF p.Pro200Arg (c.599C>G) in the general population?

ARAF p.Pro200Arg (c.599C>G) is ultra-rare (popmax 0.0136%, nfe) (gnomAD).

What do computational predictors say about ARAF p.Pro200Arg (c.599C>G)?

AlphaMissense predicts likely benign (score 0.1149) — an in-silico prediction, not a clinical call.

ARAF p.Pro200Arg

c.599C>G · rs780758789 · VCV2402017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1149	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.33	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 3.9	phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 2,114 bp · p 0.077 · regional, not allelic
Overall
CADD	17.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0136% European (non-Finnish) · 120/884,233 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0108%

Overall 0.0102% 121/1,189,969 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0136%	7,369
Remaining individualsnot grpmax-eligible	0.00214%	46,744

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: ARAF
Protein: p.Pro200Arg
Coding: c.599C>G
MANE Select: NM_001654
dbSNP: rs780758789
Type: single nucleotide variant
Location: chrX:47566680 (GRCh38)
Structure: AlphaFold pLDDT 70.99 · 7 PDB
Residue 200: the 'disordered' region

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

Similar variants

ARAF p.His191Tyr Uncertain significance ★★ ⚠ same type
ARAF p.Ala334= Benign ★★ same type
ARAF p.Leu471= Benign ★★ same type
ARAF c.97-7C>T Uncertain significance ★ same type
ARAF p.Ala110Val Uncertain significance ★ ⚠ same type
ARAF p.Ala261Val Uncertain significance ★ ⚠ same type
ARAF p.Ala48Pro Uncertain significance ★ ⚠ same type
ARAF p.Arg151Cys 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/araf-p-pro200arg (accessed [today's date]).

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