Is AMPD1 p.Ala21= (c.63T>C) pathogenic?

AMPD1 p.Ala21= (c.63T>C) is classified Likely benign in AMPD1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-03-02). Very rare (popmax 0.000424%, nfe).

How common is AMPD1 p.Ala21= (c.63T>C) in the general population?

AMPD1 p.Ala21= (c.63T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

AMPD1 p.Ala21=

c.63T>C · rs151258843 · VCV559259

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.1	GERP 1.2, phastCons 0.99
Overall
CADD	9.034	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,030 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00041% 6/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)grpmax	0.000424%	236,006

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala21=
Coding: c.63T>C
MANE Select: NM_000036
dbSNP: rs151258843
Type: single nucleotide variant
Location: chr1:114688713 (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

Similar variants

AMPD1 p.Ala21Val Uncertain significance ★ same residue
AMPD1 p.Gln653Ter Pathogenic/Likely pathogenic ★★ same type
AMPD1 c.1388+5G>A Uncertain significance ★★ same type
AMPD1 c.1974+1G>A Uncertain significance ★★ same type
AMPD1 c.-42C>T Uncertain significance ★★ ⚠ same type
AMPD1 p.Ala308Thr Uncertain significance ★★ ⚠ same type
AMPD1 p.Ala489Thr Uncertain significance ★★ ⚠ same type
AMPD1 p.Ala578Thr 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/ampd1-p-ala21 (accessed [today's date]).

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