Is AVEN p.Asn197Asp (c.589A>G) pathogenic?

AVEN p.Asn197Asp (c.589A>G) is classified Uncertain significance in AVEN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: ambiguous (0.4719); Ultra-rare (popmax 0.015%, amr).

How common is AVEN p.Asn197Asp (c.589A>G) in the general population?

AVEN p.Asn197Asp (c.589A>G) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about AVEN p.Asn197Asp (c.589A>G)?

AlphaMissense predicts ambiguous (score 0.4719) — an in-silico prediction, not a clinical call.

AVEN p.Asn197Asp

c.589A>G · rs776286550 · VCV2372380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Computational evidence

Protein change
AlphaMissense	0.4719	ambiguous
REVEL	0.362	indeterminate
SaProt	LLR -10.85	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 172 kb · p 2.1e-15 · regional, not allelic
Overall
CADD	24.5	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 0.015% Admixed American · 9/59,886 alleles

Filtering AF 0.00775% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.0023% 37/1,611,274 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,654
European (non-Finnish)	0.00238%	42,083

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.Asn197Asp
Coding: c.589A>G
MANE Select: NM_020371
dbSNP: rs776286550
Type: single nucleotide variant
Location: chr15:33870958 (GRCh38)
Gene constraint: LOEUF 1.172 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.86

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-asn197asp (accessed [today's date]).

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