Is VIM p.Arg378His (c.1133G>A) pathogenic?

VIM p.Arg378His (c.1133G>A) is classified Benign in VIM (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.174); Ultra-rare (popmax 0.0164%, mid); Associated with cataract 30.

What condition is associated with VIM p.Arg378His (c.1133G>A)?

VIM p.Arg378His (c.1133G>A) is associated with cataract 30 (ClinVar).

How common is VIM p.Arg378His (c.1133G>A) in the general population?

VIM p.Arg378His (c.1133G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about VIM p.Arg378His (c.1133G>A)?

AlphaMissense predicts likely benign (score 0.174) — an in-silico prediction, not a clinical call.

VIM p.Arg378His

c.1133G>A · rs761834421 · VCV3255373

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.174 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 30

Computational evidence

Protein change
AlphaMissense	0.174	likely benign
REVEL	0.719	pathogenic-leaning
SaProt	LLR -11.27	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,480 bp · p 0.038 · regional, not allelic
Overall
CADD	34.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00143% 23/1,613,606 alleles · ultra-rare exomes 16/1,461,396 · genomes 7/152,210 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.0133%	7,493
South Asian	0.00329%	30,363
Admixed American	0.00167%	59,964
Remaining individualsnot grpmax-eligible	0.0016%	62,452
European (non-Finnish)	0.000593%	168,568

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: VIM
Protein: p.Arg378His
Coding: c.1133G>A
MANE Select: NM_003380
dbSNP: rs761834421
Type: single nucleotide variant
Location: chr10:17235293 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 78.05 · 26 PDB
Residue 378: the if rod domain; the 'coil 2' region

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

Disease context

cataract 30 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VIM p.Arg45His Uncertain significance ★★ ⚠ same condition
VIM p.Asp360Glu Uncertain significance ★★ ⚠ same condition
VIM p.Leu164Val Uncertain significance ★★ ⚠ same condition
VIM p.Thr458Ala Uncertain significance ★★ ⚠ same condition
VIM p.Val272Ile Uncertain significance ★★ ⚠ same condition
VIM c.1008+18A>G Benign/Likely benign ★★ same condition
VIM c.1009-10C>T Benign ★★ same condition
VIM c.1360-18G>T Likely benign ★★ same condition

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/vim-p-arg378his (accessed [today's date]).

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