Is AVIL p.Ala9Ser (c.25G>T) pathogenic?

AVIL p.Ala9Ser (c.25G>T) is classified Uncertain significance in AVIL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: likely benign (0.0995); Ultra-rare (popmax 0.0246%, nfe).

How common is AVIL p.Ala9Ser (c.25G>T) in the general population?

AVIL p.Ala9Ser (c.25G>T) is ultra-rare (popmax 0.0246%, nfe) (gnomAD).

What do computational predictors say about AVIL p.Ala9Ser (c.25G>T)?

AlphaMissense predicts likely benign (score 0.0995) — an in-silico prediction, not a clinical call.

AVIL p.Ala9Ser

c.25G>T · rs148203782 · VCV3132395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0995 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0246%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0995	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -3.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 18 kb · p 9.4e-05 · regional, not allelic
Overall
CADD	18.1	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 0.0246% European (non-Finnish) · 290/1,179,996 alleles

Filtering AF 0.0222% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0213%

Overall 0.0189% 305/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0246%	4,069
African / African-American	0.0133%	7,493
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Admixed American	0.00167%	59,986

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: AVIL
Protein: p.Ala9Ser
Coding: c.25G>T
MANE Select: NM_006576
dbSNP: rs148203782
Type: single nucleotide variant
Location: chr12:57816016 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.82 · 1 PDB
Residue 9: the 'core' region

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

Similar variants

AVIL p.Arg199Ter Likely pathogenic ★★ same type
AVIL p.Asn777Lys Uncertain significance ★★ ⚠ same type
AVIL p.Gly577Ser Uncertain significance ★★ ⚠ same type
AVIL p.Gly626Ser Uncertain significance ★★ ⚠ same type
AVIL p.Ile250Thr Uncertain significance ★★ ⚠ same type
AVIL c.1194+202C>T Benign ★★ same type
AVIL c.2151+142A>G Benign ★★ same type
AVIL c.67-155C>T Benign ★★ 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/avil-p-ala9ser (accessed [today's date]).

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