Is EFS p.Arg335Trp (c.1003C>T) pathogenic?

EFS p.Arg335Trp (c.1003C>T) is classified Uncertain significance in EFS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely pathogenic (0.6592); Rare (popmax 0.291%, mid).

How common is EFS p.Arg335Trp (c.1003C>T) in the general population?

EFS p.Arg335Trp (c.1003C>T) is rare (popmax 0.291%, mid) (gnomAD).

What do computational predictors say about EFS p.Arg335Trp (c.1003C>T)?

AlphaMissense predicts likely pathogenic (score 0.6592) — an in-silico prediction, not a clinical call.

EFS p.Arg335Trp

c.1003C>T · rs147068550 · VCV3087601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6592 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.291%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6592	likely pathogenic
REVEL	0.234	benign-leaning
SaProt	LLR -9.62	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP -3.5, phastCons 0.98
Regional constraint	o/e 0.98	unconstrained · MANE · 7,796 bp · p 0.65 · regional, not allelic
Overall
CADD	21.5	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 0.291% Middle Eastern · 16/5,502 alleles

Filtering AF 0.182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.149%

Overall 0.0163% 260/1,591,788 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.291%	344
Ashkenazi Jewishnot grpmax-eligible	0.234%	428
Remaining individualsnot grpmax-eligible	0.0504%	1,985
East Asian	0.0338%	2,957
European (non-Finnish)	0.0106%	9,444
African / African-American	0.00673%	14,850
South Asian	0.00226%	44,245
Admixed American	0.00175%	57,244

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.Arg335Trp
Coding: c.1003C>T
MANE Select: NM_005864
dbSNP: rs147068550
Type: single nucleotide variant
Location: chr14:23359475 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.71
Residue 335: the 'disordered' region

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

Similar variants

EFS p.Arg335Leu 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-arg335trp (accessed [today's date]).

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