Is CALR3 p.Val92Phe (c.274G>T) pathogenic?

CALR3 p.Val92Phe (c.274G>T) is classified Uncertain significance in CALR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.6519); Very rare (popmax 8.47e-05%, nfe).

How common is CALR3 p.Val92Phe (c.274G>T) in the general population?

CALR3 p.Val92Phe (c.274G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CALR3 p.Val92Phe (c.274G>T)?

AlphaMissense predicts likely pathogenic (score 0.6519) — an in-silico prediction, not a clinical call.

CALR3 p.Val92Phe

c.274G>T · VCV4218383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6519 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6519	likely pathogenic
REVEL	0.604	indeterminate
SaProt	LLR -12.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Pangolin	Δ0.22	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.53	GERP 0.11, phastCons 0.5
Regional constraint	o/e 0.95	unconstrained · MANE · 17 kb · p 0.24 · regional, not allelic
Overall
CADD	24.9	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 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.84e-05% 1/1,461,884 alleles · very rare

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: CALR3
Protein: p.Val92Phe
Coding: c.274G>T
MANE Select: NM_145046
Type: single nucleotide variant
Location: chr19:16490490 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43
Residue 92: the 'n-domain' region

Full CALR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALR3 p.Val92Ile Uncertain significance ★ ⚠ same residue
CALR3 p.Ala331Val Uncertain significance ★★ ⚠ same type
CALR3 p.Ala348Val Uncertain significance ★★ ⚠ same type
CALR3 p.Arg278Cys Uncertain significance ★★ ⚠ same type
CALR3 p.Arg278His Uncertain significance ★★ ⚠ same type
CALR3 p.Arg278Leu Uncertain significance ★★ ⚠ same type
CALR3 p.Arg308Ile Uncertain significance ★★ ⚠ same type
CALR3 p.Arg80Cys 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/calr3-p-val92phe (accessed [today's date]).

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