Is AVEN p.Gly56Ser (c.166G>A) pathogenic?

AVEN p.Gly56Ser (c.166G>A) is classified Uncertain significance in AVEN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-18). AlphaMissense: likely benign (0.2831); Very rare (popmax 0.00193%, nfe).

How common is AVEN p.Gly56Ser (c.166G>A) in the general population?

AVEN p.Gly56Ser (c.166G>A) is very rare (popmax 0.00193%, nfe) (gnomAD).

What do computational predictors say about AVEN p.Gly56Ser (c.166G>A)?

AlphaMissense predicts likely benign (score 0.2831) — an in-silico prediction, not a clinical call.

AVEN p.Gly56Ser

c.166G>A · rs1246209806 · VCV2233460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00193%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2831	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -10.70	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.075	GERP 0.91, phastCons 0.98
Regional constraint	o/e 1.38	unconstrained · MANE · 172 kb · p 2.1e-15 · regional, not allelic
Overall
CADD	16.12	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 0.00193% European (non-Finnish) · 18/934,472 alleles

Filtering AF 0.0012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000993%

Overall 0.00166% 19/1,141,502 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00193%	51,915
African / African-American	0.00166%	60,198

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.Gly56Ser
Coding: c.166G>A
MANE Select: NM_020371
dbSNP: rs1246209806
Type: single nucleotide variant
Location: chr15:34038881 (GRCh38)
Gene constraint: LOEUF 1.172 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.86
Residue 56: the 'disordered' region

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

Similar variants

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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
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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-gly56ser (accessed [today's date]).

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