Is AVEN p.Arg50Ser (c.148C>A) pathogenic?

AVEN p.Arg50Ser (c.148C>A) is classified Uncertain significance in AVEN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-11). AlphaMissense: ambiguous (0.3592); Ultra-rare (popmax 0.0421%, sas).

How common is AVEN p.Arg50Ser (c.148C>A) in the general population?

AVEN p.Arg50Ser (c.148C>A) is ultra-rare (popmax 0.0421%, sas) (gnomAD).

What do computational predictors say about AVEN p.Arg50Ser (c.148C>A)?

AlphaMissense predicts ambiguous (score 0.3592) — an in-silico prediction, not a clinical call.

AVEN p.Arg50Ser

c.148C>A · VCV3812569

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3592 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0421%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3592	ambiguous
REVEL	0.068	moderately benign-leaning
SaProt	LLR -7.49	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 10	GERP 1.2, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 172 kb · p 2.1e-15 · regional, not allelic
Overall
CADD	21.7	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 0.0421% South Asian · 10/23,742 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0174%

Overall 0.00107% 12/1,122,304 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0421%	2,374
Remaining individualsnot grpmax-eligible	0.0053%	18,857

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.Arg50Ser
Coding: c.148C>A
MANE Select: NM_020371
Type: single nucleotide variant
Location: chr15:34038899 (GRCh38)
Gene constraint: LOEUF 1.172 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.86
Residue 50: the 'disordered' region

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

Similar variants

CHRM5 p.Leu50Phe 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
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-arg50ser (accessed [today's date]).

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