Is ESS2 p.Ser7Ala (c.19T>G) pathogenic?

ESS2 p.Ser7Ala (c.19T>G) is classified Benign in ESS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0505); Low-frequency (popmax 2.8%, afr).

How common is ESS2 p.Ser7Ala (c.19T>G) in the general population?

ESS2 p.Ser7Ala (c.19T>G) is low-frequency (popmax 2.8%, afr) (gnomAD).

What do computational predictors say about ESS2 p.Ser7Ala (c.19T>G)?

AlphaMissense predicts likely benign (score 0.0505) — an in-silico prediction, not a clinical call.

ESS2 p.Ser7Ala

c.19T>G · rs114771984 · VCV709308

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0505 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.8%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0505	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.29	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 0.48	GERP 1.2, phastCons 0.001
Regional constraint	o/e 0.94	unconstrained · MANE · 10 kb · p 0.16 · regional, not allelic
Overall
CADD	5.14	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 2.8% African / African-American · 2,011/71,784 alleles

Filtering AF 2.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.66%

Overall 0.15% 2,316/1,542,878 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.8%	36
Middle Eastern	0.367%	272
Remaining individualsnot grpmax-eligible	0.218%	458
Admixed American	0.188%	532
South Asian	0.00705%	14,178
European (non-Finnish)	0.00482%	20,761

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.Ser7Ala
Coding: c.19T>G
MANE Select: NM_022719
dbSNP: rs114771984
Type: single nucleotide variant
Location: chr22:19144622 (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.Ser7Leu Uncertain significance ★ ⚠ 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-ser7ala (accessed [today's date]).

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