Is AVEN p.Pro274Ala (c.820C>G) pathogenic?

AVEN p.Pro274Ala (c.820C>G) is classified Uncertain significance in AVEN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.0712); Ultra-rare (popmax 0.0986%, afr).

How common is AVEN p.Pro274Ala (c.820C>G) in the general population?

AVEN p.Pro274Ala (c.820C>G) is ultra-rare (popmax 0.0986%, afr) (gnomAD).

What do computational predictors say about AVEN p.Pro274Ala (c.820C>G)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

AVEN p.Pro274Ala

c.820C>G · VCV4186031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0986%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	acceptor loss, 9 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.83	GERP -3.5, phastCons 0.071
Regional constraint	o/e 1.38	unconstrained · MANE · 172 kb · p 2.1e-15 · regional, not allelic
Overall
CADD	0.734	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0986% African / African-American · 74/75,046 alleles

Filtering AF 0.0805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0738%

Overall 0.00663% 107/1,614,180 alleles · ultra-rare exomes 68/1,461,886 · genomes 39/152,294 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0986%	1,014
Admixed American	0.01%	10,003
Remaining individualsnot grpmax-eligible	0.008%	12,502
European (non-Finnish)	0.00186%	53,638

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.Pro274Ala
Coding: c.820C>G
MANE Select: NM_020371
Type: single nucleotide variant
Location: chr15:33867648 (GRCh38)
Gene constraint: LOEUF 1.172 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.86
Residue 274: the 'disordered' region

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

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RYR3 p.Glu4573Gln Uncertain significance ★★ same type
RYR3 p.His4609Arg 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-pro274ala (accessed [today's date]).

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