Is AVP p.Pro43Leu (c.128C>T) pathogenic?

AVP p.Pro43Leu (c.128C>T) is classified Uncertain significance in AVP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: likely benign (0.1564); Very rare (popmax 0.00281%, eas); Associated with neurohypophyseal diabetes insipidus.

What condition is associated with AVP p.Pro43Leu (c.128C>T)?

AVP p.Pro43Leu (c.128C>T) is associated with neurohypophyseal diabetes insipidus (ClinVar).

How common is AVP p.Pro43Leu (c.128C>T) in the general population?

AVP p.Pro43Leu (c.128C>T) is very rare (popmax 0.00281%, eas) (gnomAD).

What do computational predictors say about AVP p.Pro43Leu (c.128C>T)?

AlphaMissense predicts likely benign (score 0.1564) — an in-silico prediction, not a clinical call.

AVP p.Pro43Leu

c.128C>T · VCV3587168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1564 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00281%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurohypophyseal diabetes insipidus

Computational evidence

Protein change
AlphaMissense	0.1564	likely benign
REVEL	0.738	pathogenic-leaning
SaProt	LLR -11.90	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2, phastCons 1
Overall
CADD	28.9	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 0.00281% East Asian · 1/35,612 alleles

Filtering AF 0.00013% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.4e-05%

Overall 0.000447% 6/1,341,562 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00281%	35,612
European (non-Finnish)	0.000444%	225,441

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: AVP
Protein: p.Pro43Leu
Coding: c.128C>T
MANE Select: NM_001243133 · reported on NM_000490
Type: single nucleotide variant
Location: chr20:3083171 (GRCh38)
Structure: AlphaFold pLDDT 81.16 · 27 PDB
Residue 43: the pyrin domain; an α-helix; a disulfide bond

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

Disease context

neurohypophyseal diabetes insipidus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AVP p.Pro43Ala Benign/Likely benign ★★ ⚠ same residue
AVP p.Pro43His Uncertain significance ★ ⚠ same residue
AVP p.Pro43Thr Uncertain significance ★ ⚠ same residue
NLRP3 p.Gln43Ter Uncertain significance ★ same residue
NLRP3 p.Gln43= Likely benign ★ same residue
AVP p.Ala19Thr Pathogenic ★★ ⚠ same condition
AVP p.Cys92Tyr Likely pathogenic ★★ same condition
AVP p.Gly54Arg Pathogenic ★★ same condition

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/avp-p-pro43leu (accessed [today's date]).

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