Is AMPD2 p.Tyr414= (c.1242C>T) pathogenic?

AMPD2 p.Tyr414= (c.1242C>T) is classified Conflicting classifications of pathogenicity in AMPD2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-02). Rare (popmax 0.639%, nfe); Associated with pontocerebellar hypoplasia type 9.

What condition is associated with AMPD2 p.Tyr414= (c.1242C>T)?

AMPD2 p.Tyr414= (c.1242C>T) is associated with pontocerebellar hypoplasia type 9, hereditary spastic paraplegia 63 (ClinVar).

How common is AMPD2 p.Tyr414= (c.1242C>T) in the general population?

AMPD2 p.Tyr414= (c.1242C>T) is rare (popmax 0.639%, nfe) (gnomAD).

AMPD2 p.Tyr414=

c.1242C>T · rs114727970 · VCV210136

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.639%, nfe)

Conditions

pontocerebellar hypoplasia type 9

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 · C>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP -11	GERP -3.6
Overall
CADD	3.524	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.639% European (non-Finnish) · 7,538/1,179,952 alleles

Filtering AF 0.627% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.622%

Overall 0.501% 8,091/1,613,894 alleles · rare exomes 7,629/1,461,574 · genomes 462/152,320 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.639%	157
Remaining individualsnot grpmax-eligible	0.448%	223
Admixed American	0.125%	800
Finnishnot grpmax-eligible	0.113%	887
African / African-American	0.101%	987
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,974
Middle Eastern	0.033%	3,029
South Asian	0.0275%	3,643
East Asian	0.0178%	5,609

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: AMPD2
Protein: p.Tyr414=
Coding: c.1242C>T
MANE Select: NM_001368809
dbSNP: rs114727970
Type: single nucleotide variant
Location: chr1:109628244 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 414: a turn

Full AMPD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pontocerebellar hypoplasia type 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 63

Similar variants

AMPD2 c.1698+1G>A Pathogenic/Likely pathogenic ★★ same condition
AMPD2 p.Arg353Ter Pathogenic/Likely pathogenic ★★ same condition
AMPD2 p.Arg449Ter Pathogenic/Likely pathogenic ★★ same condition
AMPD2 p.Arg620His Pathogenic/Likely pathogenic ★★ same condition
AMPD2 p.Arg789His Likely pathogenic ★★ same condition
AMPD2 p.Glu174Ter Pathogenic/Likely pathogenic ★★ same condition
AMPD2 c.1080+3G>A Uncertain significance ★★ same condition
AMPD2 c.353+3G>A 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/ampd2-p-tyr414 (accessed [today's date]).

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