Is SEC23B p.Phe559= (c.1677T>C) pathogenic?

SEC23B p.Phe559= (c.1677T>C) is classified Likely benign in SEC23B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-04). Very rare (popmax 0.00167%, amr); Associated with congenital dyserythropoietic anemia type 2.

What condition is associated with SEC23B p.Phe559= (c.1677T>C)?

SEC23B p.Phe559= (c.1677T>C) is associated with congenital dyserythropoietic anemia type 2, Cowden syndrome 7 (ClinVar).

How common is SEC23B p.Phe559= (c.1677T>C) in the general population?

SEC23B p.Phe559= (c.1677T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Congenital dyserythropoietic anemia type II inherited?

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

SEC23B p.Phe559=

c.1677T>C · rs1285410007 · VCV2923115

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

congenital dyserythropoietic anemia type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.4	GERP 1.7, phastCons 1
Overall
CADD	8.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,978 alleles

Overall 0.000127% 2/1,579,692 alleles · very rare exomes 1/1,427,446 · genomes 1/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,978
European (non-Finnish)	8.71e-05%	1,148,743

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: SEC23B
Protein: p.Phe559=
Coding: c.1677T>C
MANE Select: NM_006363
dbSNP: rs1285410007
Type: single nucleotide variant
Location: chr20:18545967 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.41
Residue 559: a UniProt-annotated variant site (in cdan2)

Full SEC23B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital dyserythropoietic anemia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cowden syndrome 7

For Congenital dyserythropoietic anemia type II (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

SEC23B p.Phe559Leu Uncertain significance ★★ ⚠ same residue
SEC23B c.1314+1G>A Likely pathogenic ★★ same condition
SEC23B c.835-2A>G Pathogenic/Likely pathogenic ★★ same condition
SEC23B p.Ala524Val Pathogenic/Likely pathogenic ★★ same condition
SEC23B p.Arg14Trp Pathogenic/Likely pathogenic ★★ same condition
SEC23B p.Arg264Ter Pathogenic ★★ same condition
SEC23B p.Arg313His Pathogenic/Likely pathogenic ★★ same condition
SEC23B p.Arg324Ter 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/sec23b-p-phe559 (accessed [today's date]).

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