Is ESCO2 p.Arg548= (c.1644C>T) pathogenic?

ESCO2 p.Arg548= (c.1644C>T) is classified Uncertain significance in ESCO2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-01-21). Absent from gnomAD v4.1; Associated with Roberts-SC phocomelia syndrome.

What condition is associated with ESCO2 p.Arg548= (c.1644C>T)?

ESCO2 p.Arg548= (c.1644C>T) is associated with Roberts-SC phocomelia syndrome (ClinVar).

How common is ESCO2 p.Arg548= (c.1644C>T) in the general population?

ESCO2 p.Arg548= (c.1644C>T) is absent from gnomAD v4.1 (gnomAD).

ESCO2 p.Arg548=

c.1644C>T · VCV4067418

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Roberts-SC phocomelia syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.25	GERP -1.1, phastCons 0.98
Overall
CADD	9.752	PHRED · no single calibrated threshold — expert panels disagree

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.Arg548=
Coding: c.1644C>T
MANE Select: NM_001017420
Type: single nucleotide variant
Location: chr8:27799687 (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

Similar variants

ESCO2 p.Arg548His Uncertain significance ★★ ⚠ same residue
ESCO2 p.Arg548Cys 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-arg548 (accessed [today's date]).

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