Is ESPN p.Ala549Val (c.1646C>T) pathogenic?

ESPN p.Ala549Val (c.1646C>T) is classified Conflicting classifications of pathogenicity in ESPN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-10-20). AlphaMissense: likely benign (0.0941); Ultra-rare (popmax 0.083%, afr); Associated with Inborn genetic diseases.

What condition is associated with ESPN p.Ala549Val (c.1646C>T)?

ESPN p.Ala549Val (c.1646C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ESPN p.Ala549Val (c.1646C>T) in the general population?

ESPN p.Ala549Val (c.1646C>T) is ultra-rare (popmax 0.083%, afr) (gnomAD).

What do computational predictors say about ESPN p.Ala549Val (c.1646C>T)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

ESPN p.Ala549Val

c.1646C>T · rs984812540 · VCV1254031

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.083%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -7.34	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 0.59	GERP 1.4, phastCons 0.053
Regional constraint	o/e 0.58	unconstrained · MANE · 3,146 bp · p 3.4e-10 · regional, not allelic
Overall
CADD	16.97	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 0.083% African / African-American · 53/63,868 alleles

Filtering AF 0.0651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0587%

Overall 0.00475% 59/1,241,388 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.083%	1,205
Remaining individualsnot grpmax-eligible	0.00657%	15,217
European (non-Finnish)	0.000301%	332,246

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.Ala549Val
Coding: c.1646C>T
MANE Select: NM_031475
dbSNP: rs984812540
Type: single nucleotide variant
Location: chr1:6448822 (GRCh38)
Gene constraint: LOEUF 1.307 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 549: 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.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.Arg339Gln 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-ala549val (accessed [today's date]).

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