Is EPB42 p.Arg554Ter (c.1660C>T) pathogenic?

EPB42 p.Arg554Ter (c.1660C>T) is classified Pathogenic in EPB42 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). Very rare (popmax 0.00263%, nfe).

How common is EPB42 p.Arg554Ter (c.1660C>T) in the general population?

EPB42 p.Arg554Ter (c.1660C>T) is very rare (popmax 0.00263%, nfe) (gnomAD).

EPB42 p.Arg554Ter

c.1660C>T · rs765829996 · VCV1912307

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

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 11 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP -0.51, phastCons 0.97
Overall
CADD	35.0	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 0.00263% European (non-Finnish) · 31/1,180,040 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00211% 34/1,614,026 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00263%	38,066
South Asian	0.0022%	45,541
African / African-American	0.00134%	74,888

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: EPB42
Protein: p.Arg554Ter
Coding: c.1660C>T
MANE Select: NM_001114134
dbSNP: rs765829996
Type: single nucleotide variant
Location: chr15:43203234 (GRCh38)
Gene constraint: LOEUF 0.771 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.35 · 13 PDB
Residue 554: a β-strand

Full EPB42 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPB42 p.Arg554Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
EPB42 p.Arg554Gly Uncertain significance ★ ⚠ same residue
EPB42 p.Arg259Ter Pathogenic/Likely pathogenic ★★ same type
EPB42 p.Arg310Gln Likely pathogenic ★★ ⚠ same type
EPB42 c.10+51G>A Uncertain significance ★★ same type
EPB42 p.Ala353Val Uncertain significance ★★ ⚠ same type
EPB42 p.Ala51Thr Uncertain significance ★★ ⚠ same type
EPB42 p.Ala566Thr Uncertain significance ★★ ⚠ same type

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/epb42-p-arg554ter (accessed [today's date]).

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