Is ESAM p.Ile205Val (c.613A>G) pathogenic?

ESAM p.Ile205Val (c.613A>G) is classified Uncertain significance in ESAM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: likely benign (0.1036); Ultra-rare (popmax 0.0107%, afr).

How common is ESAM p.Ile205Val (c.613A>G) in the general population?

ESAM p.Ile205Val (c.613A>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about ESAM p.Ile205Val (c.613A>G)?

AlphaMissense predicts likely benign (score 0.1036) — an in-silico prediction, not a clinical call.

ESAM p.Ile205Val

c.613A>G · rs532184875 · VCV3090407

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1036 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1036	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -4.80	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 -3.5
Regional constraint	o/e 0.98	unconstrained · MANE · 8,505 bp · p 0.62 · regional, not allelic
Overall
CADD	4.864	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 0.0107% African / African-American · 8/74,860 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000558% 9/1,612,774 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,358
Remaining individualsnot grpmax-eligible	0.0016%	62,446

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: ESAM
Protein: p.Ile205Val
Coding: c.613A>G
MANE Select: NM_138961
dbSNP: rs532184875
Type: single nucleotide variant
Location: chr11:124754758 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.13
Residue 205: a disulfide bond; a UniProt-annotated variant site (in nedihss); the ig-like c2-type domain

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

Similar variants

ESAM p.Val149Ala Uncertain significance ★★ ⚠ same type
ESAM c.731-9C>A Benign ★★ same type
ESAM p.Arg107Trp Likely benign ★★ ⚠ same type
ESAM p.Ile290Val Likely benign ★★ same type
ESAM p.Leu31= Likely benign ★★ same type
ESAM p.Pro181= Likely benign ★★ same type
ESAM c.451+1G>A Likely pathogenic ★ same type
ESAM c.608-1G>A Likely pathogenic ★ same type

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/esam-p-ile205val (accessed [today's date]).

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