Is AMPD1 p.Ser126Pro (c.376T>C) pathogenic?

AMPD1 p.Ser126Pro (c.376T>C) is classified Uncertain significance in AMPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-29). AlphaMissense: likely pathogenic (0.8809); Ultra-rare (popmax 0.0117%, amr); Associated with myopathy due to myoadenylate deaminase deficiency.

What condition is associated with AMPD1 p.Ser126Pro (c.376T>C)?

AMPD1 p.Ser126Pro (c.376T>C) is associated with myopathy due to myoadenylate deaminase deficiency (ClinVar).

How common is AMPD1 p.Ser126Pro (c.376T>C) in the general population?

AMPD1 p.Ser126Pro (c.376T>C) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about AMPD1 p.Ser126Pro (c.376T>C)?

AlphaMissense predicts likely pathogenic (score 0.8809) — an in-silico prediction, not a clinical call.

AMPD1 p.Ser126Pro

c.376T>C · rs1183959177 · VCV1410944

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8809 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

myopathy due to myoadenylate deaminase deficiency

Computational evidence

Protein change
AlphaMissense	0.8809	likely pathogenic
REVEL	0.146	moderately benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.9 · regional, not allelic
Overall
CADD	26.1	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 S159P vs ClinVar S126P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,998 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000434% 7/1,613,942 alleles · ultra-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.Ser126Pro
Coding: c.376T>C
MANE Select: NM_000036
dbSNP: rs1183959177
Type: single nucleotide variant
Location: chr1:114686750 (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.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
AMPD1 p.Ala616Thr 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-ser126pro (accessed [today's date]).

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