Is AVEN p.Leu353Met (c.1057C>A) pathogenic?

AVEN p.Leu353Met (c.1057C>A) is classified Uncertain significance in AVEN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.5785); Ultra-rare (popmax 0.0101%, nfe).

How common is AVEN p.Leu353Met (c.1057C>A) in the general population?

AVEN p.Leu353Met (c.1057C>A) is ultra-rare (popmax 0.0101%, nfe) (gnomAD).

What do computational predictors say about AVEN p.Leu353Met (c.1057C>A)?

AlphaMissense predicts likely pathogenic (score 0.5785) — an in-silico prediction, not a clinical call.

AVEN p.Leu353Met

c.1057C>A · VCV4644740

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5785 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5785	likely pathogenic
REVEL	0.397	indeterminate
SaProt	LLR -9.18	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.69, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 172 kb · p 2.1e-15 · regional, not allelic
Overall
CADD	24.3	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 0.0101% European (non-Finnish) · 119/1,179,888 alleles

Filtering AF 0.00859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00804%

Overall 0.00762% 123/1,613,814 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0101%	9,915
African / African-American	0.004%	24,969
Remaining individualsnot grpmax-eligible	0.0016%	62,464

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.Leu353Met
Coding: c.1057C>A
MANE Select: NM_020371
Type: single nucleotide variant
Location: chr15:33866645 (GRCh38)
Gene constraint: LOEUF 1.172 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.86
Residue 353: the 'disordered' region

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

Similar variants

AVEN p.Leu353Arg Uncertain significance ★ ⚠ same residue
CHRM5 p.Lys353Arg Uncertain significance ★ ⚠ same residue
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

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-leu353met (accessed [today's date]).

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