Is EPS15 p.Pro325Ser (c.973C>T) pathogenic?

EPS15 p.Pro325Ser (c.973C>T) is classified Uncertain significance in EPS15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.0745); Ultra-rare (popmax 0.0102%, sas).

How common is EPS15 p.Pro325Ser (c.973C>T) in the general population?

EPS15 p.Pro325Ser (c.973C>T) is ultra-rare (popmax 0.0102%, sas) (gnomAD).

What do computational predictors say about EPS15 p.Pro325Ser (c.973C>T)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

EPS15 p.Pro325Ser

c.973C>T · VCV4664933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0745	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -5.89	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 5.1	GERP 1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 163 kb · p 0.94 · regional, not allelic
Overall
CADD	18.32	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 0.0102% South Asian · 9/88,548 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00674%

Overall 0.00767% 121/1,577,548 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0102%	9,839
European (non-Finnish)	0.00866%	11,546
African / African-American	0.00674%	14,830
Remaining individualsnot grpmax-eligible	0.00656%	15,244
Admixed American	0.0051%	19,592

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.Pro325Ser
Coding: c.973C>T
MANE Select: NM_001981
Type: single nucleotide variant
Location: chr1:51440414 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.60 · 13 PDB
Residue 325: the 'interaction with dab2' 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-pro325ser (accessed [today's date]).

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