Is AMPD2 p.Thr455Met (c.1364C>T) pathogenic?

AMPD2 p.Thr455Met (c.1364C>T) is classified Uncertain significance in AMPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). AlphaMissense: ambiguous (0.4596); Very rare (popmax 0.00891%, eas).

How common is AMPD2 p.Thr455Met (c.1364C>T) in the general population?

AMPD2 p.Thr455Met (c.1364C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about AMPD2 p.Thr455Met (c.1364C>T)?

AlphaMissense predicts ambiguous (score 0.4596) — an in-silico prediction, not a clinical call.

AMPD2 p.Thr455Met

c.1364C>T · rs764701518 · VCV2580688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Computational evidence

Protein change
AlphaMissense	0.4596	ambiguous
REVEL	0.938	strongly pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,009 bp · p 8.7e-13 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T509M vs ClinVar T455M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,888 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000496% 8/1,613,290 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,222
African / African-American	0.00134%	74,902
European (non-Finnish)	0.000254%	393,342

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: AMPD2
Protein: p.Thr455Met
Coding: c.1364C>T
MANE Select: NM_001368809
dbSNP: rs764701518
Type: single nucleotide variant
Location: chr1:109628452 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 455: a β-strand

Full AMPD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMPD2 p.Thr455= Likely benign ★ same residue
AMPD2 c.1698+1G>A Pathogenic/Likely pathogenic ★★ same type
AMPD2 p.Arg353Ter Pathogenic/Likely pathogenic ★★ same type
AMPD2 p.Arg449Ter Pathogenic/Likely pathogenic ★★ same type
AMPD2 p.Arg620His Pathogenic/Likely pathogenic ★★ same type
AMPD2 p.Arg789His Likely pathogenic ★★ same type
AMPD2 p.Glu174Ter Pathogenic/Likely pathogenic ★★ same type
AMPD2 c.1080+3G>A 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/ampd2-p-thr455met (accessed [today's date]).

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