Is EFS p.Ser20Tyr (c.59C>A) pathogenic?

EFS p.Ser20Tyr (c.59C>A) is classified Uncertain significance in EFS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: ambiguous (0.5295); Ultra-rare (popmax 0.0111%, eas).

How common is EFS p.Ser20Tyr (c.59C>A) in the general population?

EFS p.Ser20Tyr (c.59C>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about EFS p.Ser20Tyr (c.59C>A)?

AlphaMissense predicts ambiguous (score 0.5295) — an in-silico prediction, not a clinical call.

EFS p.Ser20Tyr

c.59C>A · VCV4663341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5295 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Computational evidence

Protein change
AlphaMissense	0.5295	ambiguous
REVEL	0.294	indeterminate
SaProt	LLR -11.43	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 7,796 bp · p 0.65 · regional, not allelic
Overall
CADD	26.8	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 0.0111% East Asian · 5/44,870 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00322% 52/1,613,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,974
South Asian	0.00439%	22,766
European (non-Finnish)	0.00348%	28,777
Remaining individualsnot grpmax-eligible	0.0032%	31,247

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: EFS
Protein: p.Ser20Tyr
Coding: c.59C>A
MANE Select: NM_005864
Type: single nucleotide variant
Location: chr14:23360793 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.71
Residue 20: the sh3 domain

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

Similar variants

EFS p.Ser20Cys Uncertain significance ★ ⚠ same residue
EFS p.Ser20Phe Uncertain significance ★ ⚠ same residue
EFS p.Pro141= Benign ★★ same type
EFS p.Ala167Thr Uncertain significance ★ ⚠ same type
EFS p.Ala186Val Uncertain significance ★ ⚠ same type
EFS p.Ala219Asp Uncertain significance ★ ⚠ same type
EFS p.Ala262Ser Uncertain significance ★ ⚠ same type
EFS p.Ala285Ser 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/efs-p-ser20tyr (accessed [today's date]).

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