Is EFS p.Arg343His (c.1028G>A) pathogenic?

EFS p.Arg343His (c.1028G>A) is classified Uncertain significance in EFS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: likely benign (0.0694); Ultra-rare (popmax 0.0736%, mid).

How common is EFS p.Arg343His (c.1028G>A) in the general population?

EFS p.Arg343His (c.1028G>A) is ultra-rare (popmax 0.0736%, mid) (gnomAD).

What do computational predictors say about EFS p.Arg343His (c.1028G>A)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

EFS p.Arg343His

c.1028G>A · VCV3274717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0736%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -7.10	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 -0.19	GERP -3.1, phastCons 0.24
Regional constraint	o/e 0.98	unconstrained · MANE · 7,796 bp · p 0.65 · regional, not allelic
Overall
CADD	16.12	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 0.0736% Middle Eastern · 2/2,718 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00713%

Overall 0.00659% 34/515,892 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0736%	1,359
Remaining individualsnot grpmax-eligible	0.0236%	4,243
South Asian	0.0184%	5,435
East Asian	0.00858%	11,652
Admixed American	0.00615%	16,266
African / African-American	0.00485%	20,626
European (non-Finnish)	0.00439%	22,769

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: EFS
Protein: p.Arg343His
Coding: c.1028G>A
MANE Select: NM_005864
Type: single nucleotide variant
Location: chr14:23359450 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.71
Residue 343: the 'disordered' region

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

Similar variants

EFS p.Arg343Cys Uncertain significance ★ ⚠ same residue
EFS p.Pro141= Benign ★★ same type
EFS p.Ala167Thr Uncertain significance ★ ⚠ same type
EFS p.Ala186Val Uncertain significance ★ ⚠ same type
EFS p.Ala219Asp Uncertain significance ★ ⚠ same type
EFS p.Ala262Ser Uncertain significance ★ ⚠ same type
EFS p.Ala285Ser Uncertain significance ★ ⚠ same type
EFS p.Ala40Val 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/efs-p-arg343his (accessed [today's date]).

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