Is PFAS p.Ser260Pro (c.778T>C) pathogenic?

PFAS p.Ser260Pro (c.778T>C) is classified Uncertain significance in PFAS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: ambiguous (0.4143); Very rare (popmax 0.00133%, afr).

How common is PFAS p.Ser260Pro (c.778T>C) in the general population?

PFAS p.Ser260Pro (c.778T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PFAS p.Ser260Pro (c.778T>C)?

AlphaMissense predicts ambiguous (score 0.4143) — an in-silico prediction, not a clinical call.

PFAS p.Ser260Pro

c.778T>C · VCV3417139

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4143 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4143	ambiguous
REVEL	0.097	moderately benign-leaning
SaProt	LLR -5.38	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.92	GERP 0.23, phastCons 0.002
Regional constraint	o/e 1.02	unconstrained · MANE · 9,952 bp · p 0.57 · regional, not allelic
Overall
CADD	17.84	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 0.00133% African / African-American · 1/74,914 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,613,950 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,914
European (non-Finnish)	0.000847%	118,005

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: PFAS
Protein: p.Ser260Pro
Coding: c.778T>C
MANE Select: NM_012393
Type: single nucleotide variant
Location: chr17:8256364 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.52 · 3 PDB

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

Similar variants

CTC1 p.Pro9Ser Uncertain significance ★★ ⚠ same type
CTC1 p.Ser11= Uncertain significance ★★ same type
CTC1 c.33+9T>C Likely benign ★★ same type
PFAS p.Ala466Thr Benign ★★ same type
PFAS p.Arg572Gln Likely benign ★★ same type
PFAS p.Val661Met Likely benign ★★ same type
CTC1 p.Met1Val Pathogenic ★ same type
PFAS c.681-1G>A Pathogenic ★ 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/pfas-p-ser260pro (accessed [today's date]).

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