Is AMPD2 p.Ser8Cys (c.23C>G) pathogenic?

AMPD2 p.Ser8Cys (c.23C>G) is classified Uncertain significance in AMPD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0741); Very rare (popmax 0.00858%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AMPD2 p.Ser8Cys (c.23C>G)?

AMPD2 p.Ser8Cys (c.23C>G) is associated with Inborn genetic diseases, hereditary spastic paraplegia 63, pontocerebellar hypoplasia type 9 (ClinVar).

How common is AMPD2 p.Ser8Cys (c.23C>G) in the general population?

AMPD2 p.Ser8Cys (c.23C>G) is very rare (popmax 0.00858%, nfe) (gnomAD).

What do computational predictors say about AMPD2 p.Ser8Cys (c.23C>G)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

AMPD2 p.Ser8Cys

c.23C>G · rs147463318 · VCV474995

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00858%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.22	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.86, phastCons 0.026
Regional constraint	o/e 0.84	unconstrained · MANE · 4,538 bp · p 0.074 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 S62C vs ClinVar S8C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00858% European (non-Finnish) · 101/1,177,256 alleles

Filtering AF 0.00718% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00669%

Overall 0.00628% 101/1,608,178 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: AMPD2
Protein: p.Ser8Cys
Coding: c.23C>G
MANE Select: NM_001368809
dbSNP: rs147463318
Type: single nucleotide variant
Location: chr1:109621198 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 8: the 'disordered' region

Full AMPD2 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

Also linked: hereditary spastic paraplegia 63 pontocerebellar hypoplasia type 9

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-ser8cys (accessed [today's date]).

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