Is RNF168 p.Ala161fs (c.477_480del) pathogenic?

RNF168 p.Ala161fs (c.477480del) is classified Pathogenic in RNF168 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). Very rare (popmax 0.00329%, sas).

How common is RNF168 p.Ala161fs (c.477_480del) in the general population?

RNF168 p.Ala161fs (c.477_480del) is very rare (popmax 0.00329%, sas) (gnomAD).

RNF168 p.Ala161fs

c.477_480del · rs771720993 · VCV2148010

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

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 3 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP -1.1, phastCons 0.59
Overall
CADD	25.5	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 0.00329% South Asian · 3/91,086 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.0013% 21/1,614,030 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,362
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00136%	73,749
African / African-American	0.00133%	74,932

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: RNF168
Protein: p.Ala161fs
Coding: c.477_480del
MANE Select: NM_152617
dbSNP: rs771720993
Type: Deletion
Location: chr3:196487477 (GRCh38)
Gene constraint: LOEUF 1.406 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.97 · 39 PDB
Residue 161: the 'disordered' region; an α-helix

Full RNF168 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RNF168 p.Ala161Val Likely benign ★ ⚠ same residue
RNF168 p.Arg220fs Pathogenic/Likely pathogenic ★★ same type
RNF168 p.Cys50fs Pathogenic ★★ same type
RNF168 p.Ala405fs Pathogenic ★ same type
RNF168 p.Asn187fs Pathogenic ★ same type
RNF168 p.Asn488fs Likely pathogenic ★ same type
RNF168 p.Asp431fs Pathogenic ★ same type
RNF168 p.Gln442fs Likely pathogenic ★ 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/rnf168-p-ala161fs (accessed [today's date]).

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