Is AMPD1 p.Ser440Phe (c.1319C>T) pathogenic?

AMPD1 p.Ser440Phe (c.1319C>T) is classified Uncertain significance in AMPD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-09). AlphaMissense: likely pathogenic (0.926); Very rare (popmax 0.00405%, afr); Associated with myopathy due to myoadenylate deaminase deficiency.

What condition is associated with AMPD1 p.Ser440Phe (c.1319C>T)?

AMPD1 p.Ser440Phe (c.1319C>T) is associated with myopathy due to myoadenylate deaminase deficiency (ClinVar).

How common is AMPD1 p.Ser440Phe (c.1319C>T) in the general population?

AMPD1 p.Ser440Phe (c.1319C>T) is very rare (popmax 0.00405%, afr) (gnomAD).

What do computational predictors say about AMPD1 p.Ser440Phe (c.1319C>T)?

AlphaMissense predicts likely pathogenic (score 0.926) — an in-silico prediction, not a clinical call.

AMPD1 p.Ser440Phe

c.1319C>T · rs759135029 · VCV1897845

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00405%, afr)

Conditions

myopathy due to myoadenylate deaminase deficiency

Computational evidence

Protein change
AlphaMissense	0.926	likely pathogenic
REVEL	0.564	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.9 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S473F vs ClinVar S440F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00405% African / African-American · 3/74,098 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000498%

Overall 0.000434% 7/1,612,014 alleles · very rare exomes 5/1,461,892 · genomes 2/150,122 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00405%	24,699
East Asian	0.00223%	44,796
Remaining individualsnot grpmax-eligible	0.0016%	62,434
European (non-Finnish)	0.00017%	589,831

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.Ser440Phe
Coding: c.1319C>T
MANE Select: NM_000036
dbSNP: rs759135029
Type: single nucleotide variant
Location: chr1:114677420 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.84

Full AMPD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myopathy due to myoadenylate deaminase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AMPD1 p.Ser440Tyr Uncertain significance ★ same residue
AMPD1 p.Gln653Ter Pathogenic/Likely pathogenic ★★ same condition
AMPD1 c.1388+5G>A Uncertain significance ★★ same condition
AMPD1 c.1974+1G>A Uncertain significance ★★ same condition
AMPD1 c.-42C>T Uncertain significance ★★ ⚠ same condition
AMPD1 p.Ala308Thr Uncertain significance ★★ ⚠ same condition
AMPD1 p.Ala489Thr Uncertain significance ★★ ⚠ same condition
AMPD1 p.Ala578Thr 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-ser440phe (accessed [today's date]).

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