Is ABCC12 p.Cys308Arg (c.922T>C) pathogenic?

ABCC12 p.Cys308Arg (c.922T>C) is classified Uncertain significance in ABCC12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-14). AlphaMissense: ambiguous (0.347); Very rare (popmax 0.000509%, nfe).

How common is ABCC12 p.Cys308Arg (c.922T>C) in the general population?

ABCC12 p.Cys308Arg (c.922T>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about ABCC12 p.Cys308Arg (c.922T>C)?

AlphaMissense predicts ambiguous (score 0.347) — an in-silico prediction, not a clinical call.

ABCC12 p.Cys308Arg

c.922T>C · VCV3394910

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.347 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.347	ambiguous
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -9.71	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 63 kb · p 0.2 · regional, not allelic
Overall
CADD	23.0	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 0.000509% European (non-Finnish) · 6/1,179,814 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,778 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: ABCC12
Protein: p.Cys308Arg
Coding: c.922T>C
MANE Select: NM_001393797
Type: single nucleotide variant
Location: chr16:48138285 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.09
Residue 308: the abc transmembrane type-1 1 domain

Full ABCC12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCC12 p.Cys308Ser Uncertain significance ★ ⚠ same residue
ABCC12 p.Thr1080Ala Uncertain significance ★★ ⚠ same type
ABCC12 p.Arg122= Likely benign ★★ same type
ABCC12 p.Gln831Ter Likely benign ★★ same type
ABCC12 p.Glu1191Ala Benign ★★ same type
ABCC12 p.Gly164Ter Benign/Likely benign ★★ same type
ABCC12 p.Lys1344= Benign ★★ same type
ABCC12 p.Lys894Met Benign ★★ same type

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/abcc12-p-cys308arg (accessed [today's date]).

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