Is RNF216 p.Ile504Leu (c.1510A>T) pathogenic?

RNF216 p.Ile504Leu (c.1510A>T) is classified Uncertain significance in RNF216 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.0974); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with RNF216 p.Ile504Leu (c.1510A>T)?

RNF216 p.Ile504Leu (c.1510A>T) is associated with Inborn genetic diseases (ClinVar).

How common is RNF216 p.Ile504Leu (c.1510A>T) in the general population?

RNF216 p.Ile504Leu (c.1510A>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about RNF216 p.Ile504Leu (c.1510A>T)?

AlphaMissense predicts likely benign (score 0.0974) — an in-silico prediction, not a clinical call.

RNF216 p.Ile504Leu

c.1510A>T · VCV4629237

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0974	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -6.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP 3.1, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 138 kb · p 2.8e-09 · regional, not allelic
Overall
CADD	15.98	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I447L vs ClinVar I504L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,944 alleles

Overall 0.000124% 2/1,613,872 alleles · very rare exomes 0/1,461,630 · genomes 2/152,242 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,944
European (non-Finnish)	8.47e-05%	1,179,979

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: RNF216
Protein: p.Ile504Leu
Coding: c.1510A>T
MANE Select: NM_207111
Type: single nucleotide variant
Location: chr7:5721167 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.91 · 4 PDB

Full RNF216 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RNF216 p.Ala314Pro Uncertain significance ★★ ⚠ same condition
RNF216 p.Ala588Thr Uncertain significance ★★ ⚠ same condition
RNF216 p.Arg426His Uncertain significance ★★ ⚠ same condition
RNF216 p.Arg525Gln Uncertain significance ★★ ⚠ same condition
RNF216 p.Arg686Gln Uncertain significance ★★ ⚠ same condition
RNF216 p.Arg895Gln Uncertain significance ★★ ⚠ same condition
RNF216 p.Arg920Gln Uncertain significance ★★ ⚠ same condition
RNF216 p.Asn324Ser Uncertain significance ★★ ⚠ same condition

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/rnf216-p-ile504leu (accessed [today's date]).

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