Is EPS8L2 p.Pro244Leu (c.731C>T) pathogenic?

EPS8L2 p.Pro244Leu (c.731C>T) is classified Uncertain significance in EPS8L2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.1837); Rare (popmax 0.105%, afr).

How common is EPS8L2 p.Pro244Leu (c.731C>T) in the general population?

EPS8L2 p.Pro244Leu (c.731C>T) is rare (popmax 0.105%, afr) (gnomAD).

What do computational predictors say about EPS8L2 p.Pro244Leu (c.731C>T)?

AlphaMissense predicts likely benign (score 0.1837) — an in-silico prediction, not a clinical call.

EPS8L2 p.Pro244Leu

c.731C>T · VCV3509665

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1837 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1837	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -5.55	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 5.5	GERP 1.2, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 18 kb · p 2.2e-09 · regional, not allelic
Overall
CADD	22.2	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

Grpmax group 0.105% African / African-American · 77/73,016 alleles

Filtering AF 0.0865% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0794%

Overall 0.00559% 86/1,539,802 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.105%	948
Middle Eastern	0.0448%	2,234
Admixed American	0.00786%	12,731
Remaining individualsnot grpmax-eligible	0.00501%	19,948

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: EPS8L2
Protein: p.Pro244Leu
Coding: c.731C>T
MANE Select: NM_022772
Type: single nucleotide variant
Location: chr11:721315 (GRCh38)
Gene constraint: LOEUF 1.164 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 2 PDB

Full EPS8L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPS8L2 p.Glu165Ter Likely pathogenic ★★ same type
EPS8L2 p.Arg102Trp Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg193Gln Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg245Gln Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg272Trp Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg365Cys Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg506Leu Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg76Trp 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/eps8l2-p-pro244leu (accessed [today's date]).

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