Is CS p.Ser463Phe (c.1388C>T) pathogenic?

CS p.Ser463Phe (c.1388C>T) is classified Conflicting classifications of pathogenicity in CS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1723); Rare (popmax 0.246%, nfe).

How common is CS p.Ser463Phe (c.1388C>T) in the general population?

CS p.Ser463Phe (c.1388C>T) is rare (popmax 0.246%, nfe) (gnomAD).

What do computational predictors say about CS p.Ser463Phe (c.1388C>T)?

AlphaMissense predicts likely benign (score 0.1723) — an in-silico prediction, not a clinical call.

CS p.Ser463Phe

c.1388C>T · rs139054969 · VCV708211

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1723 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.246%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1723	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -13.11	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 13 kb · p 7.5e-36 · regional, not allelic
Overall
CADD	19.71	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 0.246% European (non-Finnish) · 2,897/1,178,268 alleles

Filtering AF 0.238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.235%

Overall 0.203% 3,275/1,609,866 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.246%	407
Remaining individualsnot grpmax-eligible	0.175%	572
South Asian	0.168%	594
Finnishnot grpmax-eligible	0.0766%	1,306
Admixed American	0.061%	1,640
African / African-American	0.0401%	2,495
Middle Eastern	0.0166%	6,026
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,386

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: CS
Protein: p.Ser463Phe
Coding: c.1388C>T
MANE Select: NM_004077
dbSNP: rs139054969
Type: single nucleotide variant
Location: chr12:56273097 (GRCh38)
Gene constraint: LOEUF 0.356 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.56 · 11 PDB

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

Similar variants

CS p.Leu257= Benign ★★ same type
CS p.Phe96= Benign ★★ same type
CS p.Ala2Gly Uncertain significance ★ ⚠ same type
CS p.Ala8Ser Uncertain significance ★ ⚠ same type
CS p.Arg183Gly Uncertain significance ★ ⚠ same type
CS p.Arg191Gln Uncertain significance ★ ⚠ same type
CS p.Arg218Gln Uncertain significance ★ ⚠ same type
CS p.Arg329Gln 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/cs-p-ser463phe (accessed [today's date]).

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