Is ACD p.Pro253Gln (c.758C>A) pathogenic?

ACD p.Pro253Gln (c.758C>A) is classified Uncertain significance in ACD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: likely benign (0.0886); Very rare (popmax 0.00117%, sas); Associated with Inborn genetic diseases.

What condition is associated with ACD p.Pro253Gln (c.758C>A)?

ACD p.Pro253Gln (c.758C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ACD p.Pro253Gln (c.758C>A) in the general population?

ACD p.Pro253Gln (c.758C>A) is very rare (popmax 0.00117%, sas) (gnomAD).

What do computational predictors say about ACD p.Pro253Gln (c.758C>A)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

ACD p.Pro253Gln

c.758C>A · rs752205833 · VCV3232628

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00117%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -1.9, phastCons 0.01
Regional constraint	o/e 0.89	unconstrained · MANE · 2,611 bp · p 0.011 · regional, not allelic
Overall
CADD	14.88	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 0.00117% South Asian · 1/85,666 alleles

Overall 7.01e-05% 1/1,426,238 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: ACD
Protein: p.Pro253Gln
Coding: c.758C>A
MANE Select: NM_001082486
dbSNP: rs752205833
Type: single nucleotide variant
Location: chr16:67658626 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 28 PDB

Full ACD 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

ACD p.Pro253Leu Uncertain significance ★★ ⚠ same residue
ACD p.Pro253= Likely benign ★★ same residue
ACD p.Pro253Ser Uncertain significance ★★ ⚠ same residue
ACD c.-20C>T Uncertain significance ★★ same condition
ACD c.-26T>G Uncertain significance ★★ same condition
ACD c.-29C>A Uncertain significance ★★ same condition
ACD c.-30C>T Uncertain significance ★★ same condition
ACD c.-35C>T 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/acd-p-pro253gln (accessed [today's date]).

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