Is ESAM p.Ser127Phe (c.380C>T) pathogenic?

ESAM p.Ser127Phe (c.380C>T) is classified Uncertain significance in ESAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-11). AlphaMissense: ambiguous (0.365); Very rare (popmax 8.47e-05%, nfe).

How common is ESAM p.Ser127Phe (c.380C>T) in the general population?

ESAM p.Ser127Phe (c.380C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ESAM p.Ser127Phe (c.380C>T)?

AlphaMissense predicts ambiguous (score 0.365) — an in-silico prediction, not a clinical call.

ESAM p.Ser127Phe

c.380C>T · VCV4019690

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.365 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.365	ambiguous
REVEL	0.083	moderately benign-leaning
SaProt	LLR -6.71	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -0.22, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 8,505 bp · p 0.62 · regional, not allelic
Overall
CADD	19.43	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 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 6.84e-05% 1/1,461,872 alleles · very rare

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.Ser127Phe
Coding: c.380C>T
MANE Select: NM_138961
Type: single nucleotide variant
Location: chr11:124756612 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.13
Residue 127: a UniProt-annotated variant site (in nedihss); the ig-like v-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-ser127phe (accessed [today's date]).

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