Is CCT2 p.Ala140Val (c.419C>T) pathogenic?

CCT2 p.Ala140Val (c.419C>T) is classified Uncertain significance in CCT2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-01-01). AlphaMissense: likely benign (0.1411); Ultra-rare (popmax 0.0143%, sas); Associated with inherited retinal dystrophy.

What condition is associated with CCT2 p.Ala140Val (c.419C>T)?

CCT2 p.Ala140Val (c.419C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is CCT2 p.Ala140Val (c.419C>T) in the general population?

CCT2 p.Ala140Val (c.419C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about CCT2 p.Ala140Val (c.419C>T)?

AlphaMissense predicts likely benign (score 0.1411) — an in-silico prediction, not a clinical call.

CCT2 p.Ala140Val

c.419C>T · VCV3249356

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1411 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1411	likely benign
REVEL	0.501	indeterminate
SaProt	LLR -9.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.58	donor gain · deltas
Pangolin	Δ0.35	gain · loss 0.20 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 7,571 bp · p 0.023 · regional, not allelic
Overall
CADD	32.0	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 0.0143% South Asian · 13/91,066 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00093% 15/1,613,582 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,005
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	8.48e-05%	1,179,518

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: CCT2
Protein: p.Ala140Val
Coding: c.419C>T
MANE Select: NM_006431
Type: single nucleotide variant
Location: chr12:69588235 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.85 · 71 PDB
Residue 140: an α-helix

Full CCT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCT2 p.Arg281His Uncertain significance ★★ ⚠ same condition
CCT2 p.Val256Leu Uncertain significance ⚠ same condition
CCT2 p.Ala128Thr Uncertain significance ★★ ⚠ same type
CCT2 p.Ala133Val Uncertain significance ★★ ⚠ same type
CCT2 p.Ala145Val Uncertain significance ★★ ⚠ same type
CCT2 p.Arg156Cys Uncertain significance ★★ ⚠ same type
CCT2 p.Arg255Gln Uncertain significance ★★ same type
CCT2 p.Arg255Trp 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/cct2-p-ala140val (accessed [today's date]).

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