Is KNL1 p.Pro248= (c.744G>A) pathogenic?

KNL1 p.Pro248= (c.744G>A) is classified Conflicting classifications of pathogenicity in KNL1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-08-01). Very rare (popmax 0.0052%, amr); Associated with microcephaly 4, primary, autosomal recessive.

What condition is associated with KNL1 p.Pro248= (c.744G>A)?

KNL1 p.Pro248= (c.744G>A) is associated with microcephaly 4, primary, autosomal recessive (ClinVar).

How common is KNL1 p.Pro248= (c.744G>A) in the general population?

KNL1 p.Pro248= (c.744G>A) is very rare (popmax 0.0052%, amr) (gnomAD).

KNL1 p.Pro248=

c.744G>A · rs565734208 · VCV884556

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0052%, amr)

Conditions

microcephaly 4, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -2.1, phastCons 0.89
Overall
CADD	2.49	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0052% Admixed American · 3/57,670 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00199% 32/1,605,850 alleles · very rare exomes 30/1,453,604 · genomes 2/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0052%	19,223
East Asian	0.00446%	22,401
African / African-American	0.00269%	37,206
South Asian	0.00222%	44,969
European (non-Finnish)	0.00195%	51,178

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: KNL1
Protein: p.Pro248=
Coding: c.744G>A
MANE Select: NM_144508
dbSNP: rs565734208
Type: single nucleotide variant
Location: chr15:40621008 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 40.30 · 7 PDB
Residue 248: the 'interaction with bub1 and bub1b' region; the 'may mediate oligomerization' region; an α-helix

Full KNL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 4, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KNL1 p.Pro248Leu Likely benign ★ same residue
KNL1 c.250+4A>G Uncertain significance ★★ same condition
KNL1 p.Arg1841His Uncertain significance ★★ ⚠ same condition
KNL1 p.Asn465His Uncertain significance ★★ ⚠ same condition
KNL1 p.Asp405Gly Uncertain significance ★★ ⚠ same condition
KNL1 p.Lys606Arg Uncertain significance ★★ ⚠ same condition
KNL1 p.Pro2142Leu Uncertain significance ★★ ⚠ same condition
KNL1 p.Pro2166Arg 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/knl1-p-pro248 (accessed [today's date]).

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