Is RNF216 p.Ser609Phe (c.1826C>T) pathogenic?

RNF216 p.Ser609Phe (c.1826C>T) is classified Uncertain significance in RNF216 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-04). AlphaMissense: ambiguous (0.4818); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RNF216 p.Ser609Phe (c.1826C>T)?

RNF216 p.Ser609Phe (c.1826C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RNF216 p.Ser609Phe (c.1826C>T) in the general population?

RNF216 p.Ser609Phe (c.1826C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RNF216 p.Ser609Phe (c.1826C>T)?

AlphaMissense predicts ambiguous (score 0.4818) — an in-silico prediction, not a clinical call.

RNF216 p.Ser609Phe

c.1826C>T · rs2534084843 · VCV2316771

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4818 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4818	ambiguous
REVEL	0.28	benign-leaning
SaProt	LLR -13.44	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 4.2, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 138 kb · p 2.8e-09 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S552F vs ClinVar S609F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,380 alleles

Overall 6.2e-05% 1/1,612,666 alleles · very rare exomes 1/1,460,360 · genomes 0/152,306 · 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: RNF216
Protein: p.Ser609Phe
Coding: c.1826C>T
MANE Select: NM_207111
dbSNP: rs2534084843
Type: single nucleotide variant
Location: chr7:5715060 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.91 · 4 PDB
Residue 552 UniProt numbering: a β-strand; the 'triad supradomain' region

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-ser609phe (accessed [today's date]).

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