Is RNF216 p.Pro683Ser (c.2047C>T) pathogenic?

RNF216 p.Pro683Ser (c.2047C>T) is classified Uncertain significance in RNF216 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: ambiguous (0.5089); Absent from gnomAD v4.1.

How common is RNF216 p.Pro683Ser (c.2047C>T) in the general population?

RNF216 p.Pro683Ser (c.2047C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RNF216 p.Pro683Ser (c.2047C>T)?

AlphaMissense predicts ambiguous (score 0.5089) — an in-silico prediction, not a clinical call.

RNF216 p.Pro683Ser

c.2047C>T · rs374914168 · VCV1347442

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5089 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.5089	ambiguous
REVEL	0.293	indeterminate
SaProt	LLR -10.62	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 4.4, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 138 kb · p 2.8e-09 · regional, not allelic
Overall
CADD	29.9	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 P626S vs ClinVar P683S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RNF216
Protein: p.Pro683Ser
Coding: c.2047C>T
MANE Select: NM_207111
dbSNP: rs374914168
Type: single nucleotide variant
Location: chr7:5711775 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.91 · 4 PDB
Residue 626 UniProt numbering: a turn; the 'triad supradomain' region

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

Similar variants

RNF216 p.Pro683Leu Uncertain significance ★ same residue
RNF216 p.Trp229Ter Pathogenic/Likely pathogenic ★★ same type
RNF216 p.Ala314Pro Uncertain significance ★★ ⚠ same type
RNF216 p.Ala588Thr Uncertain significance ★★ ⚠ same type
RNF216 p.Ala652Val Uncertain significance ★★ ⚠ same type
RNF216 p.Arg262His Uncertain significance ★★ ⚠ same type
RNF216 p.Arg391Thr Uncertain significance ★★ ⚠ same type
RNF216 p.Arg426His 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/rnf216-p-pro683ser (accessed [today's date]).

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