Is ESS2 p.Ser7Leu (c.20C>T) pathogenic?

ESS2 p.Ser7Leu (c.20C>T) is classified Uncertain significance in ESS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely benign (0.1281); Ultra-rare (popmax 0.0278%, afr).

How common is ESS2 p.Ser7Leu (c.20C>T) in the general population?

ESS2 p.Ser7Leu (c.20C>T) is ultra-rare (popmax 0.0278%, afr) (gnomAD).

What do computational predictors say about ESS2 p.Ser7Leu (c.20C>T)?

AlphaMissense predicts likely benign (score 0.1281) — an in-silico prediction, not a clinical call.

ESS2 p.Ser7Leu

c.20C>T · rs145030716 · VCV3090595

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1281 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0278%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1281	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -8.24	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 3.3	GERP 1.2, phastCons 0.45
Regional constraint	o/e 0.94	unconstrained · MANE · 10 kb · p 0.16 · regional, not allelic
Overall
CADD	16.37	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 0.0278% African / African-American · 20/71,856 alleles

Filtering AF 0.0184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00207% 32/1,543,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0278%	3,593
Remaining individualsnot grpmax-eligible	0.00846%	11,823
Admixed American	0.002%	49,956
South Asian	0.00118%	85,046
European (non-Finnish)	0.000438%	228,391

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: ESS2
Protein: p.Ser7Leu
Coding: c.20C>T
MANE Select: NM_022719
dbSNP: rs145030716
Type: single nucleotide variant
Location: chr22:19144621 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.41 · 5 PDB
Residue 7: the 'disordered' region

Full ESS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESS2 p.Ser7Ala Benign ★★ same residue
ESS2 p.Arg175Gln Uncertain significance ★★ ⚠ same type
ESS2 p.Asn311= Benign ★★ same type
ESS2 p.Glu234Lys Benign ★★ ⚠ same type
ESS2 p.His178= Likely benign ★★ same type
ESS2 p.Lys66= Benign/Likely benign ★★ same type
ESS2 p.Pro99Leu Benign ★★ same type
ESS2 p.Thr460= Likely benign ★★ 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/ess2-p-ser7leu (accessed [today's date]).

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