Is ESCO2 p.Ser85Phe (c.254C>T) pathogenic?

ESCO2 p.Ser85Phe (c.254C>T) is classified Uncertain significance in ESCO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-08). AlphaMissense: ambiguous (0.4259); Absent from gnomAD v4.1; Associated with Roberts-SC phocomelia syndrome.

What condition is associated with ESCO2 p.Ser85Phe (c.254C>T)?

ESCO2 p.Ser85Phe (c.254C>T) is associated with Roberts-SC phocomelia syndrome, Juberg-Hayward syndrome (ClinVar).

How common is ESCO2 p.Ser85Phe (c.254C>T) in the general population?

ESCO2 p.Ser85Phe (c.254C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ESCO2 p.Ser85Phe (c.254C>T)?

AlphaMissense predicts ambiguous (score 0.4259) — an in-silico prediction, not a clinical call.

ESCO2 p.Ser85Phe

c.254C>T · VCV3595476

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4259 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Roberts-SC phocomelia syndrome

Computational evidence

Protein change
AlphaMissense	0.4259	ambiguous
REVEL	0.339	indeterminate
SaProt	LLR -8.50	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP 0.82, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.82 · regional, not allelic
Overall
CADD	23.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ESCO2
Protein: p.Ser85Phe
Coding: c.254C>T
MANE Select: NM_001017420
Type: single nucleotide variant
Location: chr8:27776562 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 58.81

Full ESCO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Roberts-SC phocomelia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Juberg-Hayward syndrome

Similar variants

ESCO2 p.Ser85fs Pathogenic ★★ same residue
ESCO2 p.Ser85Pro Uncertain significance ★ ⚠ same residue
ESCO2 c.1013+1G>A Likely pathogenic ★★ same condition
ESCO2 c.1131+1G>A Pathogenic ★★ same condition
ESCO2 c.1131+1G>T Pathogenic ★★ same condition
ESCO2 c.1132-7A>G Pathogenic/Likely pathogenic ★★ same condition
ESCO2 c.1353+1G>T Likely pathogenic ★★ same condition
ESCO2 p.Arg169Ter Pathogenic ★★ same condition

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/esco2-p-ser85phe (accessed [today's date]).

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