Is ACD p.Ser25Arg (c.75T>G) pathogenic?

ACD p.Ser25Arg (c.75T>G) is classified Uncertain significance in ACD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-07). AlphaMissense: ambiguous (0.4028); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with ACD p.Ser25Arg (c.75T>G)?

ACD p.Ser25Arg (c.75T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ACD p.Ser25Arg (c.75T>G) in the general population?

ACD p.Ser25Arg (c.75T>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ACD p.Ser25Arg (c.75T>G)?

AlphaMissense predicts ambiguous (score 0.4028) — an in-silico prediction, not a clinical call.

ACD p.Ser25Arg

c.75T>G · rs2052976583 · VCV1730410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4028	ambiguous
REVEL	0.053	moderately benign-leaning
SaProt	LLR -4.79	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.62	GERP -2.8, phastCons 0.94
Regional constraint	o/e 0.89	unconstrained · MANE · 2,611 bp · p 0.011 · regional, not allelic
Overall
CADD	19.83	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,868 alleles

Overall 0.000124% 2/1,612,334 alleles · very rare exomes 1/1,460,246 · genomes 1/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,868
European (non-Finnish)	8.48e-05%	1,179,889

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.Ser25Arg
Coding: c.75T>G
MANE Select: NM_001082486
dbSNP: rs2052976583
Type: single nucleotide variant
Location: chr16:67660146 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 28 PDB
Residue 25: a modified residue (phosphoserine)

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.Ser25Gly Uncertain significance ★ ⚠ same residue
ACD p.Thr25Ser 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
ACD c.-36C>G 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-ser25arg (accessed [today's date]).

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