Is CGREF1 p.His149= (c.447C>T) pathogenic?

CGREF1 p.His149= (c.447C>T) is classified Likely benign in CGREF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). Very rare (popmax 0.00333%, amr).

How common is CGREF1 p.His149= (c.447C>T) in the general population?

CGREF1 p.His149= (c.447C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

CGREF1 p.His149=

c.447C>T · VCV4001975

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.89	GERP -3.3
Overall
CADD	0.698	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00248% 40/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0172%	5,820
Admixed Americangrpmax	0.00333%	30,000
East Asian	0.00223%	44,892
European (non-Finnish)	0.00203%	49,168
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,088

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CGREF1
Protein: p.His149=
Coding: c.447C>T
MANE Select: NM_006569
Type: single nucleotide variant
Location: chr2:27101784 (GRCh38)
Gene constraint: LOEUF 1.364 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.75
Residue 149: the ef-hand 2 domain

Full CGREF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KHK c.*469G>A Uncertain significance ★★ same type
KHK p.Ala230Thr Uncertain significance ★★ ⚠ same type
KHK p.Glu276Lys Uncertain significance ★★ ⚠ same type
KHK c.*540G>C Benign ★★ same type
KHK c.*580T>C Benign ★★ same type
KHK c.*754T>C Benign ★★ same type
KHK c.*767C>T Benign ★★ same type
KHK c.*79G>A 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/cgref1-p-his149 (accessed [today's date]).

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