Is CHKA p.Pro83Leu (c.248C>T) pathogenic?

CHKA p.Pro83Leu (c.248C>T) is classified Uncertain significance in CHKA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). AlphaMissense: ambiguous (0.3673); Very rare (popmax 0.00338%, amr).

How common is CHKA p.Pro83Leu (c.248C>T) in the general population?

CHKA p.Pro83Leu (c.248C>T) is very rare (popmax 0.00338%, amr) (gnomAD).

What do computational predictors say about CHKA p.Pro83Leu (c.248C>T)?

AlphaMissense predicts ambiguous (score 0.3673) — an in-silico prediction, not a clinical call.

CHKA p.Pro83Leu

c.248C>T · VCV3833021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00338%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3673	ambiguous
REVEL	0.115	moderately benign-leaning
SaProt	LLR -6.32	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 0.89, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 67 kb · p 0.94 · regional, not allelic
Overall
CADD	23.6	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 0.00338% Admixed American · 1/29,560 alleles

Overall 0.000501% 6/1,197,890 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00685%	14,597
Remaining individualsnot grpmax-eligible	0.0049%	20,422
Admixed Americangrpmax	0.00338%	29,560
European (non-Finnish)	0.000104%	958,552

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: CHKA
Protein: p.Pro83Leu
Coding: c.248C>T
MANE Select: NM_001277
Type: single nucleotide variant
Location: chr11:68120930 (GRCh38)
Gene constraint: LOEUF 0.926 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.95 · 26 PDB
Residue 83: the 'disordered' region; an α-helix

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

Similar variants

CHKA p.Glu230Lys Uncertain significance ★★ ⚠ same type
CHKA p.Arg141Trp Likely pathogenic ★ same type
CHKA p.Gly344Ter Likely pathogenic ★ same type
CHKA p.Phe341Leu Likely pathogenic ★ same type
CHKA p.Pro194Ser Likely pathogenic ★ same type
CHKA p.Ala188Thr Uncertain significance ★ ⚠ same type
CHKA p.Ala27Thr Uncertain significance ★ ⚠ same type
CHKA p.Ala385Thr 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/chka-p-pro83leu (accessed [today's date]).

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