Is CHAF1A p.Leu766Phe (c.2296C>T) pathogenic?

CHAF1A p.Leu766Phe (c.2296C>T) is classified Uncertain significance in CHAF1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1123); Very rare (popmax 0.0011%, sas).

How common is CHAF1A p.Leu766Phe (c.2296C>T) in the general population?

CHAF1A p.Leu766Phe (c.2296C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CHAF1A p.Leu766Phe (c.2296C>T)?

AlphaMissense predicts likely benign (score 0.1123) — an in-silico prediction, not a clinical call.

CHAF1A p.Leu766Phe

c.2296C>T · VCV4653215

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1123 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1123	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -4.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,368 bp · p 0.16 · regional, not allelic
Overall
CADD	19.67	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 0.0011% South Asian · 1/91,072 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,532 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	0.00017%	589,897

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: CHAF1A
Protein: p.Leu766Phe
Coding: c.2296C>T
MANE Select: NM_005483
Type: single nucleotide variant
Location: chr19:4433162 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.06 · 11 PDB
Residue 766: the 'disordered' region; the 'binds to p60' region

Full CHAF1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

UBXN6 p.Arg313Leu Uncertain significance ★★ ⚠ same type
CHAF1A p.Ala70= Benign ★★ same type
CHAF1A p.Trp668Ter Pathogenic ★ same type
CHAF1A p.Ala140Gly Uncertain significance ★ ⚠ same type
CHAF1A p.Ala16Pro Uncertain significance ★ ⚠ same type
CHAF1A p.Ala193Ser Uncertain significance ★ ⚠ same type
CHAF1A p.Ala193Thr Uncertain significance ★ ⚠ same type
CHAF1A p.Ala247Pro 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/chaf1a-p-leu766phe (accessed [today's date]).

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