Is EPS15 p.Pro710Leu (c.2129C>T) pathogenic?

EPS15 p.Pro710Leu (c.2129C>T) is classified Uncertain significance in EPS15 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.2643); Ultra-rare (popmax 0.0242%, sas).

How common is EPS15 p.Pro710Leu (c.2129C>T) in the general population?

EPS15 p.Pro710Leu (c.2129C>T) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

What do computational predictors say about EPS15 p.Pro710Leu (c.2129C>T)?

AlphaMissense predicts likely benign (score 0.2643) — an in-silico prediction, not a clinical call.

EPS15 p.Pro710Leu

c.2129C>T · rs756747774 · VCV2243390

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2643 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2643	likely benign
REVEL	0.431	indeterminate
SaProt	LLR -10.37	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 163 kb · p 0.94 · regional, not allelic
Overall
CADD	29.3	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 0.0242% South Asian · 22/90,786 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00149% 24/1,611,594 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,127
Remaining individualsnot grpmax-eligible	0.00321%	31,199

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: EPS15
Protein: p.Pro710Leu
Coding: c.2129C>T
MANE Select: NM_001981
dbSNP: rs756747774
Type: single nucleotide variant
Location: chr1:51366020 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.60 · 13 PDB
Residue 710: the '15 x 3 aa repeats of d-p-f' region

Full EPS15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPS15 p.Ala208Ser Uncertain significance ★ ⚠ same type
EPS15 p.Ala2Ser Uncertain significance ★ ⚠ same type
EPS15 p.Ala39Thr Uncertain significance ★ ⚠ same type
EPS15 p.Ala423Val Uncertain significance ★ ⚠ same type
EPS15 p.Ala4Thr Uncertain significance ★ ⚠ same type
EPS15 p.Ala560Ser Uncertain significance ★ ⚠ same type
EPS15 p.Ala613Gly Uncertain significance ★ ⚠ same type
EPS15 p.Ala667Thr 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/eps15-p-pro710leu (accessed [today's date]).

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