Is EPB42 p.Arg554Gln (c.1661G>A) pathogenic?

EPB42 p.Arg554Gln (c.1661G>A) is classified Conflicting classifications of pathogenicity in EPB42 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0593); Very rare (popmax 0.00669%, eas); Associated with hereditary spherocytosis type 5.

What condition is associated with EPB42 p.Arg554Gln (c.1661G>A)?

EPB42 p.Arg554Gln (c.1661G>A) is associated with hereditary spherocytosis type 5 (ClinVar).

How common is EPB42 p.Arg554Gln (c.1661G>A) in the general population?

EPB42 p.Arg554Gln (c.1661G>A) is very rare (popmax 0.00669%, eas) (gnomAD).

How is Hereditary spherocytosis inherited?

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

What do computational predictors say about EPB42 p.Arg554Gln (c.1661G>A)?

AlphaMissense predicts likely benign (score 0.0593) — an in-silico prediction, not a clinical call.

EPB42 p.Arg554Gln

c.1661G>A · rs150037117 · VCV316010

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0593 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spherocytosis type 5

Computational evidence

Protein change
AlphaMissense	0.0593	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.8	GERP -3.1
Regional constraint	o/e 0.84	unconstrained · MANE · 24 kb · p 3.5e-06 · regional, not allelic
Overall
CADD	0.151	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,870 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00465% 75/1,614,004 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
Admixed American	0.00667%	15,001
African / African-American	0.00534%	18,742
European (non-Finnish)	0.00517%	19,344
South Asian	0.0022%	45,532
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Arg554Gln
Coding: c.1661G>A
MANE Select: NM_001114134
dbSNP: rs150037117
Type: single nucleotide variant
Location: chr15:43203233 (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

Disease context

hereditary spherocytosis type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary spherocytosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Germany)

Similar variants

EPB42 p.Arg554Ter Pathogenic ★ same residue
EPB42 p.Arg554Gly Uncertain significance ★ ⚠ same residue
EPB42 p.Arg259Ter Pathogenic/Likely pathogenic ★★ same condition
EPB42 p.Arg310Gln Likely pathogenic ★★ ⚠ same condition
EPB42 c.10+51G>A Uncertain significance ★★ same condition
EPB42 p.Ala353Val Uncertain significance ★★ ⚠ same condition
EPB42 p.Ala51Thr Uncertain significance ★★ ⚠ same condition
EPB42 p.Ala566Thr 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/epb42-p-arg554gln (accessed [today's date]).

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