Is ABCB4 p.Thr438Met (c.1313C>T) pathogenic?

ABCB4 p.Thr438Met (c.1313C>T) is classified Uncertain significance in ABCB4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.0923); Ultra-rare (popmax 0.0227%, nfe); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB4 p.Thr438Met (c.1313C>T)?

ABCB4 p.Thr438Met (c.1313C>T) is associated with familial intrahepatic cholestasis (ClinVar).

How common is ABCB4 p.Thr438Met (c.1313C>T) in the general population?

ABCB4 p.Thr438Met (c.1313C>T) is ultra-rare (popmax 0.0227%, nfe) (gnomAD).

What do computational predictors say about ABCB4 p.Thr438Met (c.1313C>T)?

AlphaMissense predicts likely benign (score 0.0923) — an in-silico prediction, not a clinical call.

ABCB4 p.Thr438Met

c.1313C>T · rs142271471 · VCV501153

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0923 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.0923	likely benign
REVEL	0.367	indeterminate
SaProt	LLR -10.08	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -1.7
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	14.55	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 0.0227% European (non-Finnish) · 268/1,179,992 alleles

Filtering AF 0.0204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.0181% 292/1,613,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0227%	4,403
African / African-American	0.0147%	6,808
Remaining individualsnot grpmax-eligible	0.0128%	7,810
Admixed American	0.005%	19,994
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Finnishnot grpmax-eligible	0.00156%	64,008

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: ABCB4
Protein: p.Thr438Met
Coding: c.1313C>T
MANE Select: NM_000443
dbSNP: rs142271471
Type: single nucleotide variant
Location: chr7:87443362 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 438: an α-helix; the abc transporter 1 domain

Full ABCB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial intrahepatic cholestasis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCB4 p.Thr438= Benign/Likely benign ★★ same residue
ABCB4 c.2064+3A>T Likely pathogenic ★★ same condition
ABCB4 c.2682+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.2783+1G>T Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.286+1G>A Pathogenic ★★ same condition
ABCB4 c.3081+1G>C Pathogenic ★★ same condition
ABCB4 c.3486+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.3486+1G>T Pathogenic/Likely pathogenic ★★ 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/abcb4-p-thr438met (accessed [today's date]).

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