Is PAX8 p.Asp331Val (c.992A>T) pathogenic?

PAX8 p.Asp331Val (c.992A>T) is classified Uncertain significance in PAX8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: ambiguous (0.3677); Very rare (popmax 0.000848%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PAX8 p.Asp331Val (c.992A>T)?

PAX8 p.Asp331Val (c.992A>T) is associated with Inborn genetic diseases (ClinVar).

How common is PAX8 p.Asp331Val (c.992A>T) in the general population?

PAX8 p.Asp331Val (c.992A>T) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about PAX8 p.Asp331Val (c.992A>T)?

AlphaMissense predicts ambiguous (score 0.3677) — an in-silico prediction, not a clinical call.

PAX8 p.Asp331Val

c.992A>T · VCV3414571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3677 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3677	ambiguous
REVEL	0.512	indeterminate
SaProt	LLR -7.28	tolerated
Splicing
SpliceAI	Δ0.38	acceptor gain · deltas
Pangolin	Δ0.39	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 24 kb · p 0.083 · regional, not allelic
Overall
CADD	33.0	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 0.000848% European (non-Finnish) · 10/1,179,792 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00062% 10/1,613,544 alleles · very rare

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: PAX8
Protein: p.Asp331Val
Coding: c.992A>T
MANE Select: NM_003466
Type: single nucleotide variant
Location: chr2:113235489 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 58.09 · 1 PDB

Full PAX8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PAX8 p.Gln354Glu Uncertain significance ★★ ⚠ same condition
PAX8 p.Gly11Arg Uncertain significance ★★ ⚠ same condition
PAX8 p.Leu266Ser Uncertain significance ★★ ⚠ same condition
PAX8 p.Met102Ile Uncertain significance ★★ ⚠ same condition
PAX8 p.Pro321His Uncertain significance ★★ ⚠ same condition
PAX8 p.Pro409Arg Uncertain significance ★★ same condition
PAX8 p.Pro437Leu Uncertain significance ★★ ⚠ same condition
PAX8 p.Ser427Phe Uncertain significance ★★ ⚠ 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/pax8-p-asp331val (accessed [today's date]).

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