Is ESCO2 p.Phe255Ser (c.764T>C) pathogenic?

ESCO2 p.Phe255Ser (c.764T>C) is classified Benign/Likely benign in ESCO2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0654); Low-frequency (popmax 3.99%, amr); Associated with Roberts-SC phocomelia syndrome.

What condition is associated with ESCO2 p.Phe255Ser (c.764T>C)?

ESCO2 p.Phe255Ser (c.764T>C) is associated with Roberts-SC phocomelia syndrome (ClinVar).

How common is ESCO2 p.Phe255Ser (c.764T>C) in the general population?

ESCO2 p.Phe255Ser (c.764T>C) is low-frequency (popmax 3.99%, amr) (gnomAD).

What do computational predictors say about ESCO2 p.Phe255Ser (c.764T>C)?

AlphaMissense predicts likely benign (score 0.0654) — an in-silico prediction, not a clinical call.

ESCO2 p.Phe255Ser

c.764T>C · rs141631911 · VCV196300

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0654 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.99%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Roberts-SC phocomelia syndrome

Computational evidence

Protein change
AlphaMissense	0.0654	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -4.19	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 -0.27	GERP -0.67
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.82 · regional, not allelic
Overall
CADD	1.876	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 3.99% Admixed American · 2,306/57,770 alleles

Filtering AF 3.86% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.8%

Overall 0.199% 3,195/1,605,628 alleles · low-frequency exomes 2,796/1,453,358 · genomes 399/152,270 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	3.99%	25
Middle Eastern	0.897%	111
Remaining individualsnot grpmax-eligible	0.185%	540
African / African-American	0.117%	854
South Asian	0.106%	940
European (non-Finnish)	0.0448%	2,231
East Asian	0.0223%	4,485
Finnishnot grpmax-eligible	0.00156%	63,920

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: ESCO2
Protein: p.Phe255Ser
Coding: c.764T>C
MANE Select: NM_001017420
dbSNP: rs141631911
Type: single nucleotide variant
Location: chr8:27777072 (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.Phe255= Likely benign ★★ same residue
ESCO2 p.Phe255fs Pathogenic ★★ same residue
ESCO2 p.Phe255Leu 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

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-phe255ser (accessed [today's date]).

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