Is KRIT1 p.Pro41Ala (c.121C>G) pathogenic?

KRIT1 p.Pro41Ala (c.121C>G) is classified Uncertain significance in KRIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.1004); Very rare (popmax 0.000765%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KRIT1 p.Pro41Ala (c.121C>G)?

KRIT1 p.Pro41Ala (c.121C>G) is associated with Inborn genetic diseases (ClinVar).

How common is KRIT1 p.Pro41Ala (c.121C>G) in the general population?

KRIT1 p.Pro41Ala (c.121C>G) is very rare (popmax 0.000765%, nfe) (gnomAD).

What do computational predictors say about KRIT1 p.Pro41Ala (c.121C>G)?

AlphaMissense predicts likely benign (score 0.1004) — an in-silico prediction, not a clinical call.

KRIT1 p.Pro41Ala

c.121C>G · VCV4044756

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1004 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000765%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1004	likely benign
REVEL	0.521	indeterminate
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 3.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 6,702 bp · p 0.49 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000765% European (non-Finnish) · 9/1,176,352 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000621% 10/1,609,430 alleles · very rare exomes 8/1,457,468 · genomes 2/151,962 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,340
European (non-Finnish)grpmax	0.000765%	130,706

Remaining individuals 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: KRIT1
Protein: p.Pro41Ala
Coding: c.121C>G
MANE Select: NM_194454
Type: single nucleotide variant
Location: chr7:92241134 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 15 PDB
Residue 41: the 'n-terminal domain similar to nudix hydrolase domain' region

Full KRIT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KRIT1 p.Pro41= Likely benign ★ same residue
KRIT1 c.2025+3A>G Uncertain significance ★★ same condition
KRIT1 p.Arg167Cys Uncertain significance ★★ ⚠ same condition
KRIT1 p.Arg167His Uncertain significance ★★ ⚠ same condition
KRIT1 p.Arg179Gln Uncertain significance ★★ ⚠ same condition
KRIT1 p.Arg243Trp Uncertain significance ★★ ⚠ same condition
KRIT1 p.Arg306His Uncertain significance ★★ ⚠ same condition
KRIT1 p.Arg485Cys Uncertain significance ★★ ⚠ same condition

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/krit1-p-pro41ala (accessed [today's date]).

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