Is ESM1 p.Ser35Asn (c.104G>A) pathogenic?

ESM1 p.Ser35Asn (c.104G>A) is classified Likely benign in ESM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.0706); Very rare (popmax 0.00267%, afr).

How common is ESM1 p.Ser35Asn (c.104G>A) in the general population?

ESM1 p.Ser35Asn (c.104G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ESM1 p.Ser35Asn (c.104G>A)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

ESM1 p.Ser35Asn

c.104G>A · VCV4251053

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -8.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.38	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -3.4	GERP -3.8
Regional constraint	o/e 0.81	unconstrained · MANE · 6,182 bp · p 0.0029 · regional, not allelic
Overall
CADD	0.092	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 0.00267% African / African-American · 2/74,948 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,614,094 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,474
European (non-Finnish)	0.000169%	590,026

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: ESM1
Protein: p.Ser35Asn
Coding: c.104G>A
MANE Select: NM_007036
Type: single nucleotide variant
Location: chr5:54985414 (GRCh38)
Gene constraint: LOEUF 0.862 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 72.15
Residue 35: the igfbp n-terminal domain; a disulfide bond

Full ESM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESM1 p.Thr150= Benign ★★ same type
ESM1 p.Arg124Gly Uncertain significance ★ ⚠ same type
ESM1 p.Arg184Cys Uncertain significance ★ ⚠ same type
ESM1 p.Arg184His Uncertain significance ★ ⚠ same type
ESM1 p.Asp158Asn Uncertain significance ★ ⚠ same type
ESM1 p.Asp158Tyr Uncertain significance ★ ⚠ same type
ESM1 p.Cys32Gly Uncertain significance ★ ⚠ same type
ESM1 p.Gly120Asp Uncertain significance ★ ⚠ 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/esm1-p-ser35asn (accessed [today's date]).

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