Is CENPF p.Ala2139Thr (c.6415G>A) pathogenic?

CENPF p.Ala2139Thr (c.6415G>A) is classified Benign in CENPF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0709); Common (popmax 14.8%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Stromme syndrome.

What condition is associated with CENPF p.Ala2139Thr (c.6415G>A)?

CENPF p.Ala2139Thr (c.6415G>A) is associated with Stromme syndrome (ClinVar).

How is Primary ciliary dyskinesia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CENPF p.Ala2139Thr (c.6415G>A)?

AlphaMissense predicts likely benign (score 0.0709) — an in-silico prediction, not a clinical call.

CENPF p.Ala2139Thr

Q: How common is CENPF p.Ala2139Thr (c.6415G>A) in the general population?

CENPF p.Ala2139Thr (c.6415G>A) is common (popmax 14.8%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6415G>A · rs3748695 · VCV1209675

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0709 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.8%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Stromme syndrome

Computational evidence

Protein change
AlphaMissense	0.0709	likely benign
REVEL	0.058	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -4.1
Regional constraint	o/e 0.98	unconstrained · MANE · 50 kb · p 0.16 · regional, not allelic
Overall
CADD	0.69	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 14.8% South Asian · 13,442/91,076 alleles

Filtering AF 14.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.5%

Overall 6.34% 102,319/1,613,964 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	14.8%	7
Admixed American	13.8%	7
East Asian	11.5%	9
African / African-American	10.6%	9
Middle Eastern	7.23%	14
Remaining individualsnot grpmax-eligible	6.67%	15
Ashkenazi Jewishnot grpmax-eligible	5.18%	19
European (non-Finnish)	5.06%	20
Amishnot grpmax-eligible	4.17%	24
Finnishnot grpmax-eligible	2.59%	39

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: CENPF
Protein: p.Ala2139Thr
Coding: c.6415G>A
MANE Select: NM_016343
dbSNP: rs3748695
Type: single nucleotide variant
Location: chr1:214645985 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Residue 2139: the 'interaction with nde1 and ndel1' region; the '2 x 177 aa tandem repeats' region

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

Disease context

Stromme syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary ciliary dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Pakistan)

Similar variants

CENPF p.Ala2139Val Uncertain significance ★ ⚠ same residue
CENPF c.1195-2A>G Likely pathogenic ★★ same condition
CENPF c.1323+1G>A Pathogenic ★★ same condition
CENPF p.Arg1667Ter Pathogenic/Likely pathogenic ★★ same condition
CENPF p.Arg2407Ter Pathogenic/Likely pathogenic ★★ same condition
CENPF p.Arg2898Ter Pathogenic ★★ same condition
CENPF p.Arg3094Ter Likely pathogenic ★★ same condition
CENPF p.Glu1257Ter Pathogenic ★★ 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/cenpf-p-ala2139thr (accessed [today's date]).

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