Is EPB42 p.Met1Val (c.1A>G) pathogenic?

EPB42 p.Met1Val (c.1A>G) is classified Uncertain significance in EPB42 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-01). Very rare (popmax 0.00356%, nfe); Associated with hereditary spherocytosis type 5.

What condition is associated with EPB42 p.Met1Val (c.1A>G)?

EPB42 p.Met1Val (c.1A>G) is associated with hereditary spherocytosis type 5 (ClinVar).

How common is EPB42 p.Met1Val (c.1A>G) in the general population?

EPB42 p.Met1Val (c.1A>G) is very rare (popmax 0.00356%, nfe) (gnomAD).

How is Hereditary spherocytosis inherited?

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

EPB42 p.Met1Val

c.1A>G · rs755278322 · VCV2581666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Conditions

hereditary spherocytosis type 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.64	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.3, phastCons 1
Overall
CADD	23.0	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 0.00356% European (non-Finnish) · 42/1,179,784 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00317% 51/1,610,948 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00801%	12,490
European (non-Finnish)grpmax	0.00356%	28,090
Admixed American	0.00333%	29,996
East Asian	0.00223%	44,876
African / African-American	0.00133%	74,922

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Met1Val
Coding: c.1A>G
MANE Select: NM_001114134
dbSNP: rs755278322
Type: single nucleotide variant
Location: chr15:43220825 (GRCh38)
Gene constraint: LOEUF 0.771 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.35 · 13 PDB

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.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
EPB42 p.Arg155Cys Uncertain significance ★★ ⚠ same condition
EPB42 p.Arg287His 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-met1val (accessed [today's date]).

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