Is VIM p.Leu135Phe (c.403C>T) pathogenic?

VIM p.Leu135Phe (c.403C>T) is classified Uncertain significance in VIM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-11). AlphaMissense: likely pathogenic (0.9242); Ultra-rare (popmax 0.0684%, sas).

How common is VIM p.Leu135Phe (c.403C>T) in the general population?

VIM p.Leu135Phe (c.403C>T) is ultra-rare (popmax 0.0684%, sas) (gnomAD).

What do computational predictors say about VIM p.Leu135Phe (c.403C>T)?

AlphaMissense predicts likely pathogenic (score 0.9242) — an in-silico prediction, not a clinical call.

VIM p.Leu135Phe

c.403C>T · VCV3468072

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9242 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0684%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9242	likely pathogenic
REVEL	0.755	pathogenic-leaning
SaProt	LLR -12.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,480 bp · p 0.038 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0684% South Asian · 61/89,124 alleles

Filtering AF 0.0546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0496%

Overall 0.00437% 70/1,602,094 alleles · ultra-rare exomes 65/1,449,886 · genomes 5/152,208 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0684%	1,461
Remaining individualsnot grpmax-eligible	0.00805%	12,422
East Asian	0.00449%	22,257
European (non-Finnish)	0.00017%	587,361

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.Leu135Phe
Coding: c.403C>T
MANE Select: NM_003380
Type: single nucleotide variant
Location: chr10:17229825 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 78.05 · 26 PDB
Residue 135: an α-helix; the if rod domain; the 'linker 1' region

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

Similar variants

VIM p.Arg45His Uncertain significance ★★ ⚠ same type
VIM p.Asp360Glu Uncertain significance ★★ ⚠ same type
VIM p.Leu164Val Uncertain significance ★★ ⚠ same type
VIM p.Thr458Ala Uncertain significance ★★ ⚠ same type
VIM p.Val272Ile Uncertain significance ★★ ⚠ same type
VIM c.1008+18A>G Benign/Likely benign ★★ same type
VIM c.1008+99G>A Benign ★★ same type
VIM c.1009-10C>T Benign ★★ 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/vim-p-leu135phe (accessed [today's date]).

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