Is ABCC5 p.Ile412Thr (c.1235T>C) pathogenic?

ABCC5 p.Ile412Thr (c.1235T>C) is classified Uncertain significance in ABCC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely benign (0.2993); Very rare (popmax 0.00167%, amr).

How common is ABCC5 p.Ile412Thr (c.1235T>C) in the general population?

ABCC5 p.Ile412Thr (c.1235T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ABCC5 p.Ile412Thr (c.1235T>C)?

AlphaMissense predicts likely benign (score 0.2993) — an in-silico prediction, not a clinical call.

ABCC5 p.Ile412Thr

c.1235T>C · VCV3991282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2993	likely benign
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -8.52	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 72 kb · p 6.6e-23 · regional, not allelic
Overall
CADD	23.5	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 0.00167% Admixed American · 1/60,004 alleles

Overall 0.000124% 2/1,614,086 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: ABCC5
Protein: p.Ile412Thr
Coding: c.1235T>C
MANE Select: NM_005688
Type: single nucleotide variant
Location: chr3:183978564 (GRCh38)
Gene constraint: LOEUF 0.455 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.13 · 6 PDB
Residue 412: the abc transmembrane type-1 1 domain; an α-helix

Full ABCC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCC5 c.825+10G>A Benign ★★ same type
ABCC5 p.Cys594= Benign ★★ same type
ABCC5 p.Ala1008Ser Uncertain significance ★ ⚠ same type
ABCC5 p.Ala1150Thr Uncertain significance ★ ⚠ same type
ABCC5 p.Ala1182Val Uncertain significance ★ ⚠ same type
ABCC5 p.Ala1302Gly Uncertain significance ★ ⚠ same type
ABCC5 p.Ala1343Thr Uncertain significance ★ ⚠ same type
ABCC5 p.Ala1434Thr Uncertain significance ★ ⚠ 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/abcc5-p-ile412thr (accessed [today's date]).

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