Is EPOR p.Pro488Ser (c.1462C>T) pathogenic?

EPOR p.Pro488Ser (c.1462C>T) is classified Benign/Likely benign in EPOR (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.0709); Low-frequency (popmax 2.89%, amr); Associated with intellectual disability-hypotonic facies syndrome, X-linked, 1.

What condition is associated with EPOR p.Pro488Ser (c.1462C>T)?

EPOR p.Pro488Ser (c.1462C>T) is associated with intellectual disability-hypotonic facies syndrome, X-linked, 1, primary familial polycythemia due to EPO receptor mutation (ClinVar).

How common is EPOR p.Pro488Ser (c.1462C>T) in the general population?

EPOR p.Pro488Ser (c.1462C>T) is low-frequency (popmax 2.89%, amr) (gnomAD).

What do computational predictors say about EPOR p.Pro488Ser (c.1462C>T)?

AlphaMissense predicts likely benign (score 0.0709) — an in-silico prediction, not a clinical call.

EPOR p.Pro488Ser

c.1462C>T · rs142094773 · VCV268130

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0709 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.89%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability-hypotonic facies syndrome, X-linked, 1

Computational evidence

Protein change
AlphaMissense	0.0709	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -6.43	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 1.3	GERP -0.35, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,220 bp · p 0.0057 · regional, not allelic
Overall
CADD	17.83	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 2.89% Admixed American · 1,732/60,014 alleles

Filtering AF 2.77% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.73%

Overall 0.48% 7,741/1,614,162 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	2.89%	35
Finnishnot grpmax-eligible	1.22%	82
Remaining individualsnot grpmax-eligible	0.44%	227
Ashkenazi Jewishnot grpmax-eligible	0.412%	243
European (non-Finnish)	0.377%	265
South Asian	0.33%	303
Middle Eastern	0.099%	1,010
African / African-American	0.0959%	1,042
East Asian	0.00446%	22,445

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: EPOR
Protein: p.Pro488Ser
Coding: c.1462C>T
MANE Select: NM_000121
dbSNP: rs142094773
Type: single nucleotide variant
Location: chr19:11378049 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.74 · 22 PDB
Residue 488: a UniProt-annotated variant site (in); the 'disordered' region

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

Disease context

intellectual disability-hypotonic facies syndrome, X-linked, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: primary familial polycythemia due to EPO receptor mutation

Similar variants

EPOR p.Trp439Ter Pathogenic ★★ same condition
EPOR p.Pro327Leu Uncertain significance ★★ ⚠ same condition
EPOR c.115+7A>G Benign/Likely benign ★★ same condition
EPOR c.-55G>A Benign ★★ same condition
EPOR c.*35G>A Benign ★★ same condition
EPOR p.Ala186= Benign/Likely benign ★★ same condition
EPOR p.Ala219= Benign ★★ same condition
EPOR p.Arg56= Benign/Likely benign ★★ 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/epor-p-pro488ser (accessed [today's date]).

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