Is ESPN p.Pro350Arg (c.1049C>G) pathogenic?

ESPN p.Pro350Arg (c.1049C>G) is classified Conflicting classifications of pathogenicity in ESPN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.2048); Rare (popmax 0.345%, sas); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Pro350Arg (c.1049C>G)?

ESPN p.Pro350Arg (c.1049C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Pro350Arg (c.1049C>G) in the general population?

ESPN p.Pro350Arg (c.1049C>G) is rare (popmax 0.345%, sas) (gnomAD).

What do computational predictors say about ESPN p.Pro350Arg (c.1049C>G)?

AlphaMissense predicts likely benign (score 0.2048) — an in-silico prediction, not a clinical call.

ESPN p.Pro350Arg

c.1049C>G · rs143645714 · VCV227356

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2048 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.345%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2048	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -6.40	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 1.1	GERP -1.2, phastCons 0.57
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	17.7	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 0.345% South Asian · 314/91,092 alleles

Filtering AF 0.313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.301%

Overall 0.023% 372/1,614,226 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.345%	290
Ashkenazi Jewishnot grpmax-eligible	0.132%	759
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Admixed American	0.00833%	12,006
European (non-Finnish)	0.000254%	393,343

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: ESPN
Protein: p.Pro350Arg
Coding: c.1049C>G
MANE Select: NM_031475
dbSNP: rs143645714
Type: single nucleotide variant
Location: chr1:6444539 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 350: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ESPN p.Pro350Ser Benign/Likely benign ★★ same residue
ESPN p.Pro350Leu Uncertain significance ★ ⚠ same residue
ESPN p.Pro350= Likely benign ★ same residue
ESPN p.Ala139Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala23Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala484Thr Uncertain significance ★★ ⚠ same condition
ESPN p.Ala729Glu Uncertain significance ★★ ⚠ same condition
ESPN p.Arg113His Uncertain significance ★★ ⚠ 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/espn-p-pro350arg (accessed [today's date]).

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