Is FAT4 p.Ser656Pro (c.1966T>C) pathogenic?

FAT4 p.Ser656Pro (c.1966T>C) is classified Uncertain significance in FAT4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-23). AlphaMissense: likely benign (0.2336); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with FAT4 p.Ser656Pro (c.1966T>C)?

FAT4 p.Ser656Pro (c.1966T>C) is associated with Inborn genetic diseases (ClinVar).

How common is FAT4 p.Ser656Pro (c.1966T>C) in the general population?

FAT4 p.Ser656Pro (c.1966T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about FAT4 p.Ser656Pro (c.1966T>C)?

AlphaMissense predicts likely benign (score 0.2336) — an in-silico prediction, not a clinical call.

FAT4 p.Ser656Pro

c.1966T>C · rs1730743959 · VCV1363666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2336 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2336	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.3, phastCons 0.94
Regional constraint	o/e 0.98	unconstrained · MANE · 175 kb · p 0.071 · regional, not allelic
Overall
CADD	20.7	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,040 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,614,170 alleles · very rare exomes 3/1,461,894 · genomes 0/152,276 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,520
European (non-Finnish)	8.47e-05%	1,180,034

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: FAT4
Protein: p.Ser656Pro
Coding: c.1966T>C
MANE Select: NM_001291303
dbSNP: rs1730743959
Type: single nucleotide variant
Location: chr4:125318377 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Residue 656: the cadherin 6 domain

Full FAT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FAT4 p.Ser656Cys Uncertain significance ★ ⚠ same residue
FAT4 p.Ala1020Val Uncertain significance ★★ same condition
FAT4 p.Ala1032Val Uncertain significance ★★ ⚠ same condition
FAT4 p.Ala1194Thr Uncertain significance ★★ ⚠ same condition
FAT4 p.Ala132Asp Uncertain significance ★★ ⚠ same condition
FAT4 p.Ala1536Ser Uncertain significance ★★ ⚠ same condition
FAT4 p.Ala1783Thr Uncertain significance ★★ ⚠ same condition
FAT4 p.Ala1783Val Uncertain significance ★★ ⚠ 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/fat4-p-ser656pro (accessed [today's date]).

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