Is ADK p.Pro332Ser (c.994C>T) pathogenic?

ADK p.Pro332Ser (c.994C>T) is classified Uncertain significance in ADK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-20). AlphaMissense: likely benign (0.1089); Very rare (popmax 0.00271%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ADK p.Pro332Ser (c.994C>T)?

ADK p.Pro332Ser (c.994C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ADK p.Pro332Ser (c.994C>T) in the general population?

ADK p.Pro332Ser (c.994C>T) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about ADK p.Pro332Ser (c.994C>T)?

AlphaMissense predicts likely benign (score 0.1089) — an in-silico prediction, not a clinical call.

ADK p.Pro332Ser

c.994C>T · rs2548202703 · VCV2624019

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1089 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1089	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -7.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 557 kb · p 4.5e-07 · regional, not allelic
Overall
CADD	16.56	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00271% European (non-Finnish) · 32/1,179,428 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00205% 33/1,612,098 alleles · very rare exomes 33/1,460,128 · genomes 0/151,970 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00271%	36,857
Remaining individualsnot grpmax-eligible	0.0016%	62,438

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: ADK
Protein: p.Pro332Ser
Coding: c.994C>T
MANE Select: NM_006721
dbSNP: rs2548202703
Type: single nucleotide variant
Location: chr10:74708350 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.40 · 7 PDB
Residue 332: a UniProt-annotated variant site (in hmakd)

Full ADK 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

Similar variants

ADK p.Arg338Cys Uncertain significance ★★ ⚠ same condition
ADK p.Arg338His Uncertain significance ★★ ⚠ same condition
ADK p.Asn53Asp Uncertain significance ★★ ⚠ same condition
ADK p.Asp305Glu Uncertain significance ★★ ⚠ same condition
ADK p.Gln306Leu Uncertain significance ★★ ⚠ same condition
ADK p.Lys264Asn Uncertain significance ★★ same condition
ADK p.Lys307Glu Uncertain significance ★★ ⚠ same condition
ADK p.Asn240Ser 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/adk-p-pro332ser (accessed [today's date]).

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