Is RAP2C p.Phe28Leu (c.84C>A) pathogenic?

RAP2C p.Phe28Leu (c.84C>A) is classified Uncertain significance in RAP2C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 0.000113%, nfe).

How common is RAP2C p.Phe28Leu (c.84C>A) in the general population?

RAP2C p.Phe28Leu (c.84C>A) is very rare (popmax 0.000113%, nfe) (gnomAD).

What do computational predictors say about RAP2C p.Phe28Leu (c.84C>A)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

RAP2C p.Phe28Leu

c.84C>A · VCV3942813

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000113%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 2% in RAP2C
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -13.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.20	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 3.6, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 3,097 bp · p 6.1e-07 · regional, not allelic
Overall
CADD	34.0	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 0.000113% European (non-Finnish) · 1/886,608 alleles

Overall 8.37e-05% 1/1,195,156 alleles · very rare exomes 1/1,081,984 · genomes 0/113,172 · 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: RAP2C
Protein: p.Phe28Leu
Coding: c.84C>A
MANE Select: NM_001271186
Type: single nucleotide variant
Location: chrX:132217185 (GRCh38)
Structure: AlphaFold pLDDT 91.23

Full RAP2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RAP2C p.Arg2Lys Uncertain significance ★ ⚠ same type
RAP2C p.Asp174Tyr Uncertain significance ★ ⚠ same type
RAP2C p.Leu156Val Uncertain significance ★ ⚠ same type
RAP2C p.Lys73Arg Uncertain significance ★ ⚠ same type
RAP2C p.Val81Ile Uncertain significance ★ ⚠ same type
RAP2C p.Thr178= Benign ★ same type
RAP2C p.Tyr106= Likely benign ★ 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/rap2c-p-phe28leu (accessed [today's date]).

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