Is CALR p.Pro228Ser (c.682C>T) pathogenic?

CALR p.Pro228Ser (c.682C>T) is classified Benign in CALR (ClinVar, Single submitter, 2 submitters; last evaluated 2023-12-01). AlphaMissense: likely benign (0.142); Rare (popmax 0.665%, sas).

How common is CALR p.Pro228Ser (c.682C>T) in the general population?

CALR p.Pro228Ser (c.682C>T) is rare (popmax 0.665%, sas) (gnomAD).

What do computational predictors say about CALR p.Pro228Ser (c.682C>T)?

AlphaMissense predicts likely benign (score 0.142) — an in-silico prediction, not a clinical call.

CALR p.Pro228Ser

c.682C>T · rs149740908 · VCV2649360

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.142 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.665%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.142	likely benign
REVEL	0.596	indeterminate
SaProt	LLR -11.46	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,230 bp · p 0.02 · regional, not allelic
Overall
CADD	26.4	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 0.665% South Asian · 606/91,072 alleles

Filtering AF 0.622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.604%

Overall 0.0662% 1,069/1,614,154 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.665%	150
Middle Eastern	0.61%	164
Remaining individualsnot grpmax-eligible	0.104%	962
European (non-Finnish)	0.0285%	3,512
Admixed American	0.0183%	5,456
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,921
African / African-American	0.012%	8,337

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: CALR
Protein: p.Pro228Ser
Coding: c.682C>T
MANE Select: NM_004343
dbSNP: rs149740908
Type: single nucleotide variant
Location: chr19:12940432 (GRCh38)
Gene constraint: LOEUF 0.423 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.31 · 10 PDB
Residue 228: the '4 x approximate repeats' region; the 'disordered' region; the 'p-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-pro228ser (accessed [today's date]).

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