Is ESF1 p.Arg58His (c.173G>A) pathogenic?

ESF1 p.Arg58His (c.173G>A) is classified Uncertain significance in ESF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.2698); Very rare (popmax 0.0011%, nfe).

How common is ESF1 p.Arg58His (c.173G>A) in the general population?

ESF1 p.Arg58His (c.173G>A) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about ESF1 p.Arg58His (c.173G>A)?

AlphaMissense predicts likely benign (score 0.2698) — an in-silico prediction, not a clinical call.

ESF1 p.Arg58His

c.173G>A · VCV4251046

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2698	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -11.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 68 kb · p 0.033 · regional, not allelic
Overall
CADD	26.6	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 0.0011% European (non-Finnish) · 13/1,180,020 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000889% 13/1,461,878 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: ESF1
Protein: p.Arg58His
Coding: c.173G>A
MANE Select: NM_001276380
Type: single nucleotide variant
Location: chr20:13782968 (GRCh38)
Gene constraint: LOEUF 0.854 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.81

Full ESF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESF1 p.Arg58Leu Uncertain significance ★ ⚠ same residue
NDUFAF5 c.-208C>T Benign ★★ same type
ESF1 p.Ala120Thr Uncertain significance ★ ⚠ same type
ESF1 p.Ala303Thr Uncertain significance ★ ⚠ same type
ESF1 p.Ala412Ser Uncertain significance ★ ⚠ same type
ESF1 p.Ala651Ser Uncertain significance ★ ⚠ same type
ESF1 p.Ala651Thr Uncertain significance ★ ⚠ same type
ESF1 p.Ala653Thr 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/esf1-p-arg58his (accessed [today's date]).

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