Is ESCO1 p.Ser325Pro (c.973T>C) pathogenic?

ESCO1 p.Ser325Pro (c.973T>C) is classified Uncertain significance in ESCO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-28). AlphaMissense: likely benign (0.0779); Ultra-rare (popmax 0.0684%, amr).

How common is ESCO1 p.Ser325Pro (c.973T>C) in the general population?

ESCO1 p.Ser325Pro (c.973T>C) is ultra-rare (popmax 0.0684%, amr) (gnomAD).

What do computational predictors say about ESCO1 p.Ser325Pro (c.973T>C)?

AlphaMissense predicts likely benign (score 0.0779) — an in-silico prediction, not a clinical call.

ESCO1 p.Ser325Pro

c.973T>C · rs148632485 · VCV2347784

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0779 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0684%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0779	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -7.65	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 5.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 14 kb · p 0.32 · regional, not allelic
Overall
CADD	23.3	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 0.0684% Admixed American · 41/59,966 alleles

Filtering AF 0.0538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0524%

Overall 0.0459% 741/1,613,858 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0684%	1,463
European (non-Finnish)	0.0575%	1,740
African / African-American	0.016%	6,247
Remaining individualsnot grpmax-eligible	0.016%	6,251

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: ESCO1
Protein: p.Ser325Pro
Coding: c.973T>C
MANE Select: NM_052911
dbSNP: rs148632485
Type: single nucleotide variant
Location: chr18:21573871 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 52.74 · 2 PDB
Residue 325: the 'disordered' region

Full ESCO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESCO1 p.Ala213Ser Uncertain significance ★ ⚠ same type
ESCO1 p.Ala295Val Uncertain significance ★ ⚠ same type
ESCO1 p.Ala507Val Uncertain significance ★ ⚠ same type
ESCO1 p.Ala538Ser Uncertain significance ★ ⚠ same type
ESCO1 p.Ala551Pro Uncertain significance ★ ⚠ same type
ESCO1 p.Ala597Thr Uncertain significance ★ ⚠ same type
ESCO1 p.Arg120Gln Uncertain significance ★ ⚠ same type
ESCO1 p.Arg120Trp 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/esco1-p-ser325pro (accessed [today's date]).

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