Is CYRIA p.Val286Ile (c.856G>A) pathogenic?

CYRIA p.Val286Ile (c.856G>A) is classified Uncertain significance in CYRIA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-08). AlphaMissense: likely benign (0.1186); Ultra-rare (popmax 0.0165%, mid).

How common is CYRIA p.Val286Ile (c.856G>A) in the general population?

CYRIA p.Val286Ile (c.856G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CYRIA p.Val286Ile (c.856G>A)?

AlphaMissense predicts likely benign (score 0.1186) — an in-silico prediction, not a clinical call.

CYRIA p.Val286Ile

c.856G>A · VCV3270713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1186 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1186	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -7.47	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 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 6,545 bp · p 0.0049 · regional, not allelic
Overall
CADD	26.9	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,046 alleles

Overall 0.000137% 2/1,460,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,046
East Asian	0.00223%	44,830

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: CYRIA
Protein: p.Val286Ile
Coding: c.856G>A
MANE Select: NM_030797
Type: single nucleotide variant
Location: chr2:16555121 (GRCh38)
Gene constraint: LOEUF 0.615 · pLI 0.59 (gnomAD)
Structure: AlphaFold pLDDT 92.68

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

Similar variants

CYRIA p.Val286Ala Uncertain significance ★ ⚠ same residue
CYRIA p.Ala81Val Uncertain significance ★ ⚠ same type
CYRIA p.Arg140Gln Uncertain significance ★ ⚠ same type
CYRIA p.Arg166Cys Uncertain significance ★ ⚠ same type
CYRIA p.Arg319Gln Uncertain significance ★ ⚠ same type
CYRIA p.Asn180His Uncertain significance ★ ⚠ same type
CYRIA p.Asp173Asn Uncertain significance ★ ⚠ same type
CYRIA p.Asp51Glu 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/cyria-p-val286ile (accessed [today's date]).

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