Is VIM p.Ala216Thr (c.646G>A) pathogenic?

VIM p.Ala216Thr (c.646G>A) is classified Uncertain significance in VIM (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1495); Ultra-rare (popmax 0.076%, afr); Associated with cataract 30.

What condition is associated with VIM p.Ala216Thr (c.646G>A)?

VIM p.Ala216Thr (c.646G>A) is associated with cataract 30 (ClinVar).

How common is VIM p.Ala216Thr (c.646G>A) in the general population?

VIM p.Ala216Thr (c.646G>A) is ultra-rare (popmax 0.076%, afr) (gnomAD).

What do computational predictors say about VIM p.Ala216Thr (c.646G>A)?

AlphaMissense predicts likely benign (score 0.1495) — an in-silico prediction, not a clinical call.

VIM p.Ala216Thr

c.646G>A · rs138235394 · VCV3047409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1495 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.076%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 30

Computational evidence

Protein change
AlphaMissense	0.1495	likely benign
REVEL	0.679	pathogenic-leaning
SaProt	LLR -7.22	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP -0.83, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,480 bp · p 0.038 · regional, not allelic
Overall
CADD	26.1	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 0.076% African / African-American · 57/75,012 alleles

Filtering AF 0.0601% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0545%

Overall 0.00366% 59/1,614,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.076%	1,316
Admixed American	0.00167%	60,026
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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.Ala216Thr
Coding: c.646G>A
MANE Select: NM_003380
dbSNP: rs138235394
Type: single nucleotide variant
Location: chr10:17233608 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 78.05 · 26 PDB
Residue 216: an α-helix; the if rod domain; the 'coil 1b' 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-ala216thr (accessed [today's date]).

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