Is AVEN p.Gly12Arg (c.34G>A) pathogenic?

AVEN p.Gly12Arg (c.34G>A) is classified Uncertain significance in AVEN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-01). AlphaMissense: likely pathogenic (0.653); Very rare (popmax 0.000652%, nfe).

How common is AVEN p.Gly12Arg (c.34G>A) in the general population?

AVEN p.Gly12Arg (c.34G>A) is very rare (popmax 0.000652%, nfe) (gnomAD).

What do computational predictors say about AVEN p.Gly12Arg (c.34G>A)?

AlphaMissense predicts likely pathogenic (score 0.653) — an in-silico prediction, not a clinical call.

AVEN p.Gly12Arg

c.34G>A · VCV3467421

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000652%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.653	likely pathogenic
REVEL	0.224	benign-leaning
SaProt	LLR -8.49	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 172 kb · p 2.1e-15 · regional, not allelic
Overall
CADD	17.19	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000652% European (non-Finnish) · 6/920,648 alleles

Filtering AF 0.000234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000154%

Overall 0.000534% 6/1,124,096 alleles · very rare

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: AVEN
Protein: p.Gly12Arg
Coding: c.34G>A
MANE Select: NM_020371
Type: single nucleotide variant
Location: chr15:34039013 (GRCh38)
Gene constraint: LOEUF 1.172 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.86
Residue 12: the 'disordered' region

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

Similar variants

RYR3 p.Ala4568Pro Uncertain significance ★★ ⚠ same type
RYR3 p.Ala4594Val Uncertain significance ★★ ⚠ same type
RYR3 p.Ala4650Thr Uncertain significance ★★ ⚠ same type
RYR3 p.Arg4862His Uncertain significance ★★ ⚠ same type
RYR3 p.Glu4573Gln Uncertain significance ★★ same type
RYR3 p.His4609Arg Uncertain significance ★★ ⚠ same type
RYR3 p.Ile4604Thr Uncertain significance ★★ ⚠ same type
RYR3 p.Lys4579Arg 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/aven-p-gly12arg (accessed [today's date]).

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