Is ESF1 p.Arg342Cys (c.1024C>T) pathogenic?

ESF1 p.Arg342Cys (c.1024C>T) is classified Uncertain significance in ESF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). AlphaMissense: likely benign (0.2028); Very rare (popmax 0.00447%, sas).

How common is ESF1 p.Arg342Cys (c.1024C>T) in the general population?

ESF1 p.Arg342Cys (c.1024C>T) is very rare (popmax 0.00447%, sas) (gnomAD).

What do computational predictors say about ESF1 p.Arg342Cys (c.1024C>T)?

AlphaMissense predicts likely benign (score 0.2028) — an in-silico prediction, not a clinical call.

ESF1 p.Arg342Cys

c.1024C>T · VCV3276447

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2028	likely benign
REVEL	0.429	indeterminate
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 68 kb · p 0.033 · regional, not allelic
Overall
CADD	24.1	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 0.00447% South Asian · 4/89,456 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.00168% 27/1,605,320 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00447%	22,364
European (non-Finnish)	0.00187%	53,464
Admixed American	0.0017%	58,910

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.Arg342Cys
Coding: c.1024C>T
MANE Select: NM_001276380
Type: single nucleotide variant
Location: chr20:13775884 (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.Arg342His 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-arg342cys (accessed [today's date]).

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