Is EPB41 p.Pro699Ser (c.2095C>T) pathogenic?

EPB41 p.Pro699Ser (c.2095C>T) is classified Uncertain significance in EPB41 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-14). AlphaMissense: likely benign (0.1215); Absent from gnomAD v4.1; Associated with EPB41-related disorder.

What condition is associated with EPB41 p.Pro699Ser (c.2095C>T)?

EPB41 p.Pro699Ser (c.2095C>T) is associated with EPB41-related disorder (ClinVar).

How common is EPB41 p.Pro699Ser (c.2095C>T) in the general population?

EPB41 p.Pro699Ser (c.2095C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPB41 p.Pro699Ser (c.2095C>T)?

AlphaMissense predicts likely benign (score 0.1215) — an in-silico prediction, not a clinical call.

EPB41 p.Pro699Ser

c.2095C>T · rs2548658985 · VCV2633802

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1215 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

EPB41-related disorder

Computational evidence

Protein change
AlphaMissense	0.1215	likely benign
REVEL	0.413	indeterminate
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 97 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPB41
Protein: p.Pro699Ser
Coding: c.2095C>T
MANE Select: NM_001376013
dbSNP: rs2548658985
Type: single nucleotide variant
Location: chr1:29065069 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.72 · 3 PDB
Residue 699: the 'spectrin--actin-binding' region

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

Disease context

EPB41-related disorder

Similar variants

EPB41 p.Arg554Ter Pathogenic/Likely pathogenic ★★ same condition
EPB41 p.Gln516Ter Likely pathogenic ★ same condition
EPB41 p.Glu676Ter Likely pathogenic ★ same condition
EPB41 p.Ser551Ter Likely pathogenic ★ same condition
EPB41 c.681+9G>A Likely benign same condition
EPB41 c.829+8G>C Likely benign same condition
EPB41 p.Arg700Gln Likely benign same condition
EPB41 p.Asp672= Likely benign 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-pro699ser (accessed [today's date]).

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