Is AVEN p.Arg5Leu (c.14G>T) pathogenic?

AVEN p.Arg5Leu (c.14G>T) is classified Uncertain significance in AVEN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: ambiguous (0.546); Ultra-rare (popmax 0.0388%, eas).

How common is AVEN p.Arg5Leu (c.14G>T) in the general population?

AVEN p.Arg5Leu (c.14G>T) is ultra-rare (popmax 0.0388%, eas) (gnomAD).

What do computational predictors say about AVEN p.Arg5Leu (c.14G>T)?

AlphaMissense predicts ambiguous (score 0.546) — an in-silico prediction, not a clinical call.

AVEN p.Arg5Leu

c.14G>T · rs1159700972 · VCV2390773

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.546 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0388%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.546	ambiguous
REVEL	0.036	moderately benign-leaning
SaProt	LLR -9.48	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -1, phastCons 0.99
Regional constraint	o/e 1.38	unconstrained · MANE · 172 kb · p 2.1e-15 · regional, not allelic
Overall
CADD	18.66	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 0.0388% East Asian · 7/18,046 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.0126% 141/1,118,982 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0388%	2,578
European (non-Finnish)	0.0135%	7,403
Remaining individualsnot grpmax-eligible	0.0135%	7,420
African / African-American	0.00668%	14,966
South Asian	0.00388%	25,762

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.Arg5Leu
Coding: c.14G>T
MANE Select: NM_020371
dbSNP: rs1159700972
Type: single nucleotide variant
Location: chr15:34039033 (GRCh38)
Gene constraint: LOEUF 1.172 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.86
Residue 5: the 'disordered' region

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

Similar variants

AVEN p.Arg5= Likely benign ★ 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
RYR3 p.Ile4604Thr 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-arg5leu (accessed [today's date]).

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