Is EPB41 p.Arg554Ter (c.1660C>T) pathogenic?

EPB41 p.Arg554Ter (c.1660C>T) is classified Pathogenic/Likely pathogenic in EPB41 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-09). Very rare (popmax 0.000169%, nfe); Associated with EPB41-related disorders.

What condition is associated with EPB41 p.Arg554Ter (c.1660C>T)?

EPB41 p.Arg554Ter (c.1660C>T) is associated with EPB41-related disorders, elliptocytosis 1 (ClinVar).

How common is EPB41 p.Arg554Ter (c.1660C>T) in the general population?

EPB41 p.Arg554Ter (c.1660C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

EPB41 p.Arg554Ter

c.1660C>T · rs2548448730 · VCV1951469

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

EPB41-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 21
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.81	GERP -1.2, phastCons 0.98
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,044 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,822 alleles · very rare

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: EPB41
Protein: p.Arg554Ter
Coding: c.1660C>T
MANE Select: NM_001376013
dbSNP: rs2548448730
Type: single nucleotide variant
Location: chr1:29053127 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.72 · 3 PDB
Residue 554: the 'hydrophilic' region; the 'disordered' region

Full EPB41 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

EPB41-related disorders

Also linked: elliptocytosis 1

Similar variants

EPB41 p.Arg554Gln Uncertain significance ★ ⚠ same residue
EPB41 p.Arg554Gly Uncertain significance ★ ⚠ same residue
EPB41 p.Arg471Ter Pathogenic/Likely pathogenic ★★ same condition
EPB41 p.Arg715Ter Pathogenic ★★ same condition
EPB41 p.Gln274Ter Pathogenic ★★ same condition
EPB41 p.Tyr331Ter Pathogenic/Likely pathogenic ★★ same condition
EPB41 p.Ala259Val Uncertain significance ★★ ⚠ same condition
EPB41 p.Ala502Val 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/epb41-p-arg554ter (accessed [today's date]).

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