Is ESS2 p.Ala6Val (c.17C>T) pathogenic?

ESS2 p.Ala6Val (c.17C>T) is classified Uncertain significance in ESS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.0887); Ultra-rare (popmax 0.0123%, eas).

How common is ESS2 p.Ala6Val (c.17C>T) in the general population?

ESS2 p.Ala6Val (c.17C>T) is ultra-rare (popmax 0.0123%, eas) (gnomAD).

What do computational predictors say about ESS2 p.Ala6Val (c.17C>T)?

AlphaMissense predicts likely benign (score 0.0887) — an in-silico prediction, not a clinical call.

ESS2 p.Ala6Val

c.17C>T · rs756509847 · VCV2600163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0887 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0887	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -7.66	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 -0.067	GERP -2.5
Regional constraint	o/e 0.94	unconstrained · MANE · 10 kb · p 0.16 · regional, not allelic
Overall
CADD	6.909	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 0.0123% East Asian · 5/40,584 alleles

Filtering AF 0.00482% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00311%

Overall 0.0026% 40/1,535,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0123%	8,117
Admixed American	0.00616%	16,246
African / African-American	0.0028%	35,695
European (non-Finnish)	0.00246%	40,660
Remaining individualsnot grpmax-eligible	0.0017%	58,760
South Asian	0.00119%	84,220

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.Ala6Val
Coding: c.17C>T
MANE Select: NM_022719
dbSNP: rs756509847
Type: single nucleotide variant
Location: chr22:19144624 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.41 · 5 PDB
Residue 6: the 'disordered' region

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

Similar variants

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.Ser7Ala 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-ala6val (accessed [today's date]).

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