Is ABCB6 p.Phe565Ser (c.1694T>C) pathogenic?

ABCB6 p.Phe565Ser (c.1694T>C) is classified Uncertain significance in ABCB6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-12). AlphaMissense: likely pathogenic (0.616); Ultra-rare (popmax 0.066%, mid); Associated with dyschromatosis universalis hereditaria 3.

What condition is associated with ABCB6 p.Phe565Ser (c.1694T>C)?

ABCB6 p.Phe565Ser (c.1694T>C) is associated with dyschromatosis universalis hereditaria 3 (ClinVar).

How common is ABCB6 p.Phe565Ser (c.1694T>C) in the general population?

ABCB6 p.Phe565Ser (c.1694T>C) is ultra-rare (popmax 0.066%, mid) (gnomAD).

How is Dyschromatosis universalis hereditaria inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCB6 p.Phe565Ser (c.1694T>C)?

AlphaMissense predicts likely pathogenic (score 0.616) — an in-silico prediction, not a clinical call.

ABCB6 p.Phe565Ser

c.1694T>C · rs201713868 · VCV2054878

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.616 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyschromatosis universalis hereditaria 3

Computational evidence

Protein change
AlphaMissense	0.616	likely pathogenic
REVEL	0.97	strongly pathogenic-leaning
SaProt	LLR -16.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00712% 115/1,614,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,516
Admixed American	0.0233%	4,288
South Asian	0.0143%	7,006
Remaining individualsnot grpmax-eligible	0.0112%	8,929
European (non-Finnish)	0.00653%	15,325

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: ABCB6
Protein: p.Phe565Ser
Coding: c.1694T>C
MANE Select: NM_005689
dbSNP: rs201713868
Type: single nucleotide variant
Location: chr2:219213464 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 565: an α-helix

Full ABCB6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dyschromatosis universalis hereditaria 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dyschromatosis universalis hereditaria (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ABCB6 p.Glu220Val Uncertain significance ★★ ⚠ same condition
ABCB6 c.688-9C>T Benign/Likely benign ★★ same condition
ABCB6 c.1452+2T>A Likely pathogenic ★ same condition
ABCB6 c.1864-4A>G Uncertain significance ★ same condition
ABCB6 p.Arg375Trp Conflicting classifications of pathogenicity ★ ⚠ same condition
ABCB6 p.Asn677Tyr Uncertain significance ★ ⚠ same condition
ABCB6 p.Thr787Ala Uncertain significance ★ ⚠ same condition
ABCB6 p.Trp64Cys 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/abcb6-p-phe565ser (accessed [today's date]).

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