Is SEC23B p.Arg554fs (c.1660del) pathogenic?

SEC23B p.Arg554fs (c.1660del) is classified Pathogenic/Likely pathogenic in SEC23B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-02). Very rare (popmax 0.00878%, sas); Associated with congenital dyserythropoietic anemia type 2.

What condition is associated with SEC23B p.Arg554fs (c.1660del)?

SEC23B p.Arg554fs (c.1660del) is associated with congenital dyserythropoietic anemia type 2, Cowden syndrome 7 (ClinVar).

How common is SEC23B p.Arg554fs (c.1660del) in the general population?

SEC23B p.Arg554fs (c.1660del) is very rare (popmax 0.00878%, sas) (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.Arg554fs

c.1660del · rs781770571 · VCV2433272

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Conditions

congenital dyserythropoietic anemia type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00878% South Asian · 8/91,078 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.000496% 8/1,614,158 alleles · very rare exomes 8/1,461,888 · genomes 0/152,270 · joint denominator

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.Arg554fs
Coding: c.1660del
MANE Select: NM_006363
dbSNP: rs781770571
Type: Deletion
Location: chr20:18543166 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.41
Residue 554: 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.Arg554Ter Pathogenic ★★ same residue
SEC23B p.Arg554= Likely benign ★ same residue
SEC23B c.1511+2_1511+5del Likely pathogenic ★★ same condition
SEC23B p.Ala717fs Pathogenic/Likely pathogenic ★★ same condition
SEC23B p.Glu415fs Pathogenic/Likely pathogenic ★★ same condition
SEC23B p.His631fs Pathogenic/Likely pathogenic ★★ same condition
SEC23B c.1404+20_1404+21del Benign ★★ same condition
SEC23B c.1314_1314+10del 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-arg554fs (accessed [today's date]).

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