Is AMPD1 p.Phe375Leu (c.1125C>G) pathogenic?

AMPD1 p.Phe375Leu (c.1125C>G) is classified Uncertain significance in AMPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-07). AlphaMissense: likely pathogenic (0.9996); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AMPD1 p.Phe375Leu (c.1125C>G)?

AMPD1 p.Phe375Leu (c.1125C>G) is associated with Inborn genetic diseases (ClinVar).

How common is AMPD1 p.Phe375Leu (c.1125C>G) in the general population?

AMPD1 p.Phe375Leu (c.1125C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AMPD1 p.Phe375Leu (c.1125C>G)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

AMPD1 p.Phe375Leu

c.1125C>G · rs2526352270 · VCV2323328

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 1% in AMPD1
REVEL	0.819	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.9 · regional, not allelic
Overall
CADD	24.7	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F408L vs ClinVar F375L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,010 alleles

Overall 6.84e-05% 1/1,461,848 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: AMPD1
Protein: p.Phe375Leu
Coding: c.1125C>G
MANE Select: NM_000036
dbSNP: rs2526352270
Type: single nucleotide variant
Location: chr1:114678009 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.84
Residue 375: a binding site

Full AMPD1 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

AMPD1 c.-42C>T Uncertain significance ★★ ⚠ same condition
AMPD1 p.Ala489Thr Uncertain significance ★★ ⚠ same condition
AMPD1 p.Ala578Thr Uncertain significance ★★ ⚠ same condition
AMPD1 p.Ala616Thr Uncertain significance ★★ ⚠ same condition
AMPD1 p.Arg167Gln Uncertain significance ★★ ⚠ same condition
AMPD1 p.Arg167Trp Uncertain significance ★★ same condition
AMPD1 p.Arg18His Uncertain significance ★★ ⚠ same condition
AMPD1 p.Arg196Gln 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/ampd1-p-phe375leu (accessed [today's date]).

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