Is RHBDF2 p.Phe143fs (c.428del) pathogenic?

RHBDF2 p.Phe143fs (c.428del) is classified Uncertain significance in RHBDF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-31). Ultra-rare (popmax 0.0133%, amr).

How common is RHBDF2 p.Phe143fs (c.428del) in the general population?

RHBDF2 p.Phe143fs (c.428del) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

RHBDF2 p.Phe143fs

c.428del · VCV3625555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.8	GERP 0.81, phastCons 1
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,008 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000558% 9/1,613,568 alleles · ultra-rare exomes 7/1,461,320 · genomes 2/152,248 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,501
African / African-American	0.00133%	74,944

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: RHBDF2
Protein: p.Phe143fs
Coding: c.428del
MANE Select: NM_001005498
Type: Deletion
Location: chr17:76479122 (GRCh38)
Gene constraint: LOEUF 0.545 · pLI 0.15 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.53 · 5 PDB

Full RHBDF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RHBDF2 p.Leu464_Asp467del Uncertain significance ★ same type
RHBDF2 p.Ser266fs Uncertain significance ★ same type
RHBDF2 p.Trp801fs 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/rhbdf2-p-phe143fs (accessed [today's date]).

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