Is CHAF1A p.Phe487Leu (c.1461C>A) pathogenic?

CHAF1A p.Phe487Leu (c.1461C>A) is classified Uncertain significance in CHAF1A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-14). AlphaMissense: likely pathogenic (0.6255); Ultra-rare (popmax 0.0822%, mid).

How common is CHAF1A p.Phe487Leu (c.1461C>A) in the general population?

CHAF1A p.Phe487Leu (c.1461C>A) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

What do computational predictors say about CHAF1A p.Phe487Leu (c.1461C>A)?

AlphaMissense predicts likely pathogenic (score 0.6255) — an in-silico prediction, not a clinical call.

CHAF1A p.Phe487Leu

c.1461C>A · rs758852937 · VCV2461864

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6255 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6255	likely pathogenic
REVEL	0.016	strongly benign-leaning
SaProt	LLR -4.04	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.9
Regional constraint	o/e 0.68	unconstrained · MANE · 11 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	0.007	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 0.0822% Middle Eastern · 5/6,084 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00248% 40/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,217
Remaining individualsnot grpmax-eligible	0.008%	12,497
Admixed American	0.00333%	30,005
African / African-American	0.00267%	37,469
European (non-Finnish)	0.0022%	45,386

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.Phe487Leu
Coding: c.1461C>A
MANE Select: NM_005483
dbSNP: rs758852937
Type: single nucleotide variant
Location: chr19:4428747 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.06 · 11 PDB
Residue 487: an α-helix

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-phe487leu (accessed [today's date]).

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