Is AMPD3 p.Phe457Leu (c.1369T>C) pathogenic?

AMPD3 p.Phe457Leu (c.1369T>C) is classified Uncertain significance in AMPD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.9715); Ultra-rare (popmax 0.0333%, afr).

How common is AMPD3 p.Phe457Leu (c.1369T>C) in the general population?

AMPD3 p.Phe457Leu (c.1369T>C) is ultra-rare (popmax 0.0333%, afr) (gnomAD).

What do computational predictors say about AMPD3 p.Phe457Leu (c.1369T>C)?

AlphaMissense predicts likely pathogenic (score 0.9715) — an in-silico prediction, not a clinical call.

AMPD3 p.Phe457Leu

c.1369T>C · VCV4640288

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9715 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9715	likely pathogenic
REVEL	0.677	pathogenic-leaning
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 0.75, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 44 kb · p 2.4e-05 · regional, not allelic
Overall
CADD	27.7	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 0.0333% African / African-American · 25/75,050 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00198% 32/1,614,156 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0333%	3,002
Admixed American	0.00333%	30,009
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000339%	295,004

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.Phe457Leu
Coding: c.1369T>C
MANE Select: NM_001025389
Type: single nucleotide variant
Location: chr11:10495672 (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

Similar variants

AMPD3 c.1135-5C>A Uncertain significance ★★ same type
AMPD3 c.1135-6C>G Uncertain significance ★★ same type
AMPD3 c.1267-3C>T Uncertain significance ★★ same type
AMPD3 c.*287T>C Uncertain significance ★★ same type
AMPD3 c.*75C>T Uncertain significance ★★ same type
AMPD3 p.Ala141= Uncertain significance ★★ same type
AMPD3 p.Arg426Trp Uncertain significance ★★ ⚠ same type
AMPD3 p.Arg576= 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/ampd3-p-phe457leu (accessed [today's date]).

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