Is AVL9 p.Pro125Arg (c.374C>G) pathogenic?

AVL9 p.Pro125Arg (c.374C>G) is classified Uncertain significance in AVL9 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: likely pathogenic (0.9684); Very rare (popmax 0.0062%, nfe).

How common is AVL9 p.Pro125Arg (c.374C>G) in the general population?

AVL9 p.Pro125Arg (c.374C>G) is very rare (popmax 0.0062%, nfe) (gnomAD).

What do computational predictors say about AVL9 p.Pro125Arg (c.374C>G)?

AlphaMissense predicts likely pathogenic (score 0.9684) — an in-silico prediction, not a clinical call.

AVL9 p.Pro125Arg

c.374C>G · rs374465783 · VCV2339913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9684 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0062%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9684	likely pathogenic
REVEL	0.767	pathogenic-leaning
SaProt	LLR -14.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 88 kb · p 0.00067 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0062% European (non-Finnish) · 72/1,161,080 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00462%

Overall 0.00459% 73/1,589,756 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0062%	16,126
Remaining individualsnot grpmax-eligible	0.00162%	61,618

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: AVL9
Protein: p.Pro125Arg
Coding: c.374C>G
MANE Select: NM_015060
dbSNP: rs374465783
Type: single nucleotide variant
Location: chr7:32551335 (GRCh38)
Gene constraint: LOEUF 0.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.73
Residue 125: the udenn domain

Full AVL9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AVL9 c.215-1G>A Uncertain significance ★ same type
AVL9 p.Ala510Val Uncertain significance ★ ⚠ same type
AVL9 p.Ala558Val Uncertain significance ★ ⚠ same type
AVL9 p.Arg105Lys Uncertain significance ★ ⚠ same type
AVL9 p.Arg242Gln Uncertain significance ★ ⚠ same type
AVL9 p.Arg242Trp Uncertain significance ★ ⚠ same type
AVL9 p.Arg321Cys Uncertain significance ★ ⚠ same type
AVL9 p.Arg427Gln 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/avl9-p-pro125arg (accessed [today's date]).

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