Is CFAP65 p.Ser1656Pro (c.4966T>C) pathogenic?

CFAP65 p.Ser1656Pro (c.4966T>C) is classified Benign in CFAP65 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-11-15). AlphaMissense: likely benign (0.073); Low-frequency (popmax 1.37%, afr).

How common is CFAP65 p.Ser1656Pro (c.4966T>C) in the general population?

CFAP65 p.Ser1656Pro (c.4966T>C) is low-frequency (popmax 1.37%, afr) (gnomAD).

What do computational predictors say about CFAP65 p.Ser1656Pro (c.4966T>C)?

AlphaMissense predicts likely benign (score 0.073) — an in-silico prediction, not a clinical call.

CFAP65 p.Ser1656Pro

c.4966T>C · rs115409821 · VCV775819

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.073 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.37%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.073	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -6.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.67	GERP 0.79
Regional constraint	o/e 0.99	unconstrained · MANE · 23 kb · p 0.76 · regional, not allelic
Overall
CADD	11.7	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 1.37% African / African-American · 1,024/74,886 alleles

Filtering AF 1.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.27%

Overall 0.0701% 1,130/1,612,990 alleles · low-frequency exomes 550/1,461,032 · genomes 580/151,958 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.37%	73
Remaining individualsnot grpmax-eligible	0.0801%	1,249
Admixed American	0.0783%	1,276
Middle Eastern	0.0362%	2,759
South Asian	0.0022%	45,516
European (non-Finnish)	0.000424%	235,985

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: CFAP65
Protein: p.Ser1656Pro
Coding: c.4966T>C
MANE Select: NM_194302
dbSNP: rs115409821
Type: single nucleotide variant
Location: chr2:219005519 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.03
Residue 1656: a UniProt-annotated variant site (in spgf40); the 'disordered' region

Full CFAP65 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFAP65 p.Arg1231= Benign ★★ same type
CFAP65 p.Arg1545Gln Benign ★★ same type
CFAP65 p.Arg760Gln Benign ★★ same type
CFAP65 p.Asp1313= Likely benign ★★ same type
CFAP65 p.Leu1127= Benign/Likely benign ★★ same type
CFAP65 p.Leu1523= Benign/Likely benign ★★ same type
CFAP65 p.Leu1906= Benign/Likely benign ★★ same type
CFAP65 p.Lys1805= Likely benign ★★ 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/cfap65-p-ser1656pro (accessed [today's date]).

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