Is AMPD3 p.Pro499Leu (c.1496C>T) pathogenic?

AMPD3 p.Pro499Leu (c.1496C>T) is classified Uncertain significance in AMPD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.8557); Very rare (popmax 0.0011%, sas); Associated with Erythrocyte AMP deaminase deficiency.

What condition is associated with AMPD3 p.Pro499Leu (c.1496C>T)?

AMPD3 p.Pro499Leu (c.1496C>T) is associated with Erythrocyte AMP deaminase deficiency (ClinVar).

How common is AMPD3 p.Pro499Leu (c.1496C>T) in the general population?

AMPD3 p.Pro499Leu (c.1496C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about AMPD3 p.Pro499Leu (c.1496C>T)?

AlphaMissense predicts likely pathogenic (score 0.8557) — an in-silico prediction, not a clinical call.

AMPD3 p.Pro499Leu

c.1496C>T · rs1446342474 · VCV878486

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8557 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Erythrocyte AMP deaminase deficiency

Computational evidence

Protein change
AlphaMissense	0.8557	likely pathogenic
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -10.37	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 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 44 kb · p 2.4e-05 · regional, not allelic
Overall
CADD	29.8	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 0.0011% South Asian · 1/91,078 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,613,924 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,078
European (non-Finnish)	0.000847%	117,996

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: AMPD3
Protein: p.Pro499Leu
Coding: c.1496C>T
MANE Select: NM_001025389
dbSNP: rs1446342474
Type: single nucleotide variant
Location: chr11:10496877 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.74

Full AMPD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Erythrocyte AMP deaminase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AMPD3 c.1135-5C>A Uncertain significance ★★ same condition
AMPD3 c.1135-6C>G Uncertain significance ★★ same condition
AMPD3 c.1267-3C>T Uncertain significance ★★ same condition
AMPD3 c.*287T>C Uncertain significance ★★ same condition
AMPD3 c.*75C>T Uncertain significance ★★ same condition
AMPD3 p.Ala141= Uncertain significance ★★ same condition
AMPD3 p.Arg426Trp Uncertain significance ★★ ⚠ same condition
AMPD3 p.Arg576= 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/ampd3-p-pro499leu (accessed [today's date]).

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