Is CHAF1B p.Ser520Phe (c.1559C>T) pathogenic?

CHAF1B p.Ser520Phe (c.1559C>T) is classified Uncertain significance in CHAF1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.088); Very rare (popmax 0.00927%, nfe).

How common is CHAF1B p.Ser520Phe (c.1559C>T) in the general population?

CHAF1B p.Ser520Phe (c.1559C>T) is very rare (popmax 0.00927%, nfe) (gnomAD).

What do computational predictors say about CHAF1B p.Ser520Phe (c.1559C>T)?

AlphaMissense predicts likely benign (score 0.088) — an in-silico prediction, not a clinical call.

CHAF1B p.Ser520Phe

c.1559C>T · VCV4227651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.088 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00927%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.088	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -9.97	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 1	GERP 0.4
Regional constraint	o/e 1.08	unconstrained · MANE · 3,368 bp · p 0.22 · regional, not allelic
Overall
CADD	15.45	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 0.00927% European (non-Finnish) · 109/1,175,886 alleles

Filtering AF 0.00785% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0073%

Overall 0.00702% 113/1,609,472 alleles · very rare exomes 103/1,457,260 · genomes 10/152,212 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00927%	10,788
Admixed American	0.00333%	30,001
Remaining individualsnot grpmax-eligible	0.00321%	31,170

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: CHAF1B
Protein: p.Ser520Phe
Coding: c.1559C>T
MANE Select: NM_005441
Type: single nucleotide variant
Location: chr21:36415360 (GRCh38)
Gene constraint: LOEUF 0.27 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.50 · 11 PDB
Residue 520: the 'disordered' region

Full CHAF1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHAF1B p.Leu486= Benign ★★ same type
CHAF1B p.Lys506Gln Benign ★★ same type
CHAF1B p.Pro415Leu Benign ★★ same type
CHAF1B p.Thr507Met Benign ★★ same type
MPP7 p.Ala106Thr Likely benign ★★ same type
CHAF1B p.Ala105Thr Uncertain significance ★ ⚠ same type
CHAF1B p.Ala218Val Uncertain significance ★ ⚠ same type
CHAF1B p.Ala478Val 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/chaf1b-p-ser520phe (accessed [today's date]).

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