Is RNF216 p.Val249Phe (c.745G>T) pathogenic?

RNF216 p.Val249Phe (c.745G>T) is classified Uncertain significance in RNF216 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-01). AlphaMissense: likely benign (0.1262); Rare (popmax 0.218%, eas).

How common is RNF216 p.Val249Phe (c.745G>T) in the general population?

RNF216 p.Val249Phe (c.745G>T) is rare (popmax 0.218%, eas) (gnomAD).

What do computational predictors say about RNF216 p.Val249Phe (c.745G>T)?

AlphaMissense predicts likely benign (score 0.1262) — an in-silico prediction, not a clinical call.

RNF216 p.Val249Phe

c.745G>T · rs200838092 · VCV1982602

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1262 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.218%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1262	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -7.19	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 1.8	GERP 4.4, phastCons 0.16
Regional constraint	o/e 1.18	unconstrained · MANE · 138 kb · p 2.8e-09 · regional, not allelic
Overall
CADD	18.39	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 V192F vs ClinVar V249F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.218% East Asian · 98/44,880 alleles

Filtering AF 0.183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.17%

Overall 0.0135% 218/1,614,072 alleles · rare exomes 199/1,461,842 · genomes 19/152,230 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.218%	458
South Asian	0.0582%	1,718
Middle Eastern	0.033%	3,029
Remaining individualsnot grpmax-eligible	0.0064%	15,627
European (non-Finnish)	0.00517%	19,344

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.Val249Phe
Coding: c.745G>T
MANE Select: NM_207111
dbSNP: rs200838092
Type: single nucleotide variant
Location: chr7:5741272 (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

Similar variants

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
RNF216 p.Arg525Gln 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-val249phe (accessed [today's date]).

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