Is EPB42 p.Pro367Leu (c.1100C>T) pathogenic?

EPB42 p.Pro367Leu (c.1100C>T) is classified Uncertain significance in EPB42 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). AlphaMissense: ambiguous (0.4244); Very rare (popmax 0.0011%, sas); Associated with hereditary spherocytosis type 5.

What condition is associated with EPB42 p.Pro367Leu (c.1100C>T)?

EPB42 p.Pro367Leu (c.1100C>T) is associated with hereditary spherocytosis type 5 (ClinVar).

How common is EPB42 p.Pro367Leu (c.1100C>T) in the general population?

EPB42 p.Pro367Leu (c.1100C>T) is very rare (popmax 0.0011%, sas) (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.Pro367Leu (c.1100C>T)?

AlphaMissense predicts ambiguous (score 0.4244) — an in-silico prediction, not a clinical call.

EPB42 p.Pro367Leu

c.1100C>T · VCV4078596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4244 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary spherocytosis type 5

Computational evidence

Protein change
AlphaMissense	0.4244	ambiguous
REVEL	0.529	indeterminate
SaProt	LLR -12.57	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 24 kb · p 3.5e-06 · regional, not allelic
Overall
CADD	26.8	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 0.0011% South Asian · 1/91,074 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000868% 14/1,613,820 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,244
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	0.000932%	107,275

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.Pro367Leu
Coding: c.1100C>T
MANE Select: NM_001114134
Type: single nucleotide variant
Location: chr15:43207417 (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 367: 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.Pro367Arg 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
EPB42 p.Arg155Cys 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-pro367leu (accessed [today's date]).

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