Is CALR p.Val110Ala (c.329T>C) pathogenic?

CALR p.Val110Ala (c.329T>C) is classified Uncertain significance in CALR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: likely pathogenic (0.6799); Absent from gnomAD v4.1.

How common is CALR p.Val110Ala (c.329T>C) in the general population?

CALR p.Val110Ala (c.329T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALR p.Val110Ala (c.329T>C)?

AlphaMissense predicts likely pathogenic (score 0.6799) — an in-silico prediction, not a clinical call.

CALR p.Val110Ala

c.329T>C · VCV3342043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6799 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6799	likely pathogenic
REVEL	0.484	indeterminate
SaProt	LLR -12.17	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,230 bp · p 0.02 · regional, not allelic
Overall
CADD	26.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CALR
Protein: p.Val110Ala
Coding: c.329T>C
MANE Select: NM_004343
Type: single nucleotide variant
Location: chr19:12939563 (GRCh38)
Gene constraint: LOEUF 0.423 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.31 · 10 PDB
Residue 110: a disulfide bond; a β-strand; the 'n-domain' region

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

Similar variants

CALR c.193+41C>G Benign ★★ same type
CALR c.194-41A>G Benign ★★ same type
CALR c.817-9C>T Benign/Likely benign ★★ same type
CALR c.960+128C>T Benign ★★ same type
CALR c.960+290A>G Benign ★★ same type
CALR c.961-239G>A Benign ★★ same type
CALR c.-21T>C Benign ★★ same type
CALR c.*54G>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/calr-p-val110ala (accessed [today's date]).

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