Is ESPN p.Arg339Gln (c.1016G>A) pathogenic?

ESPN p.Arg339Gln (c.1016G>A) is classified Uncertain significance in ESPN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-12). AlphaMissense: likely benign (0.0903); Very rare (popmax 0.00492%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Arg339Gln (c.1016G>A)?

ESPN p.Arg339Gln (c.1016G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Arg339Gln (c.1016G>A) in the general population?

ESPN p.Arg339Gln (c.1016G>A) is very rare (popmax 0.00492%, nfe) (gnomAD).

What do computational predictors say about ESPN p.Arg339Gln (c.1016G>A)?

AlphaMissense predicts likely benign (score 0.0903) — an in-silico prediction, not a clinical call.

ESPN p.Arg339Gln

c.1016G>A · rs148390614 · VCV163411

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00492%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0903	likely benign
REVEL	0.526	indeterminate
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.4	GERP 0.24, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 0.002 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00492% European (non-Finnish) · 58/1,180,028 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00384% 62/1,614,062 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00492%	20,345
South Asian	0.0022%	45,543
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,940

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.Arg339Gln
Coding: c.1016G>A
MANE Select: NM_031475
dbSNP: rs148390614
Type: single nucleotide variant
Location: chr1:6444506 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 339: 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.Arg339Trp Uncertain significance ★★ ⚠ 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
ESPN p.Arg335Cys Uncertain significance ★★ ⚠ same condition
ESPN p.Arg478Cys 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-arg339gln (accessed [today's date]).

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