Is ALB p.Leu556= (c.1668C>T) pathogenic?

ALB p.Leu556= (c.1668C>T) is classified Benign in ALB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). Common (popmax 58.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with hyperthyroxinemia, familial dysalbuminemic.

What condition is associated with ALB p.Leu556= (c.1668C>T)?

ALB p.Leu556= (c.1668C>T) is associated with hyperthyroxinemia, familial dysalbuminemic (ClinVar).

ALB p.Leu556=

Q: How common is ALB p.Leu556= (c.1668C>T) in the general population?

ALB p.Leu556= (c.1668C>T) is common (popmax 58.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1668C>T · rs962004 · VCV349639

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 58.2%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

hyperthyroxinemia, familial dysalbuminemic

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.047	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP -2, phastCons 0.95
Overall
CADD	11.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 58.2% European (non-Finnish) · 686,356/1,178,866 alleles

Filtering AF 58.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 58.1%

Overall 55.7% 897,677/1,611,588 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	58.2%	2
Amishnot grpmax-eligible	56.8%	2
Finnishnot grpmax-eligible	55.7%	2
East Asian	53.4%	2
Remaining individualsnot grpmax-eligible	53.3%	2
South Asian	51.2%	2
Middle Eastern	46.6%	2
Ashkenazi Jewishnot grpmax-eligible	45.4%	2
Admixed American	42%	2
African / African-American	40.4%	2

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: ALB
Protein: p.Leu556=
Coding: c.1668C>T
MANE Select: NM_001319193 · reported on NM_000477
dbSNP: rs962004
Type: single nucleotide variant
Location: chr4:73419522 (GRCh38)
Structure: AlphaFold pLDDT 64.11

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

Disease context

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

Similar variants

ALB p.Ala83Gly Uncertain significance ★★ ⚠ same condition
ALB p.Arg105His Uncertain significance ★★ ⚠ same condition
ALB p.Arg23Cys Uncertain significance ★★ ⚠ same condition
ALB p.Asp37Asn Uncertain significance ★★ ⚠ same condition
ALB p.Cys384Arg Uncertain significance ★★ ⚠ same condition
ALB p.Thr491Met Uncertain significance ★★ ⚠ same condition
ALB c.1191+11T>A Benign ★★ same condition
ALB c.1290-6T>C Benign/Likely benign ★★ 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/alb-p-leu556 (accessed [today's date]).

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