Is PFAS p.Pro617Ser (c.1849C>T) pathogenic?

PFAS p.Pro617Ser (c.1849C>T) is classified Uncertain significance in PFAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). AlphaMissense: likely benign (0.0632); Ultra-rare (popmax 0.0321%, afr).

How common is PFAS p.Pro617Ser (c.1849C>T) in the general population?

PFAS p.Pro617Ser (c.1849C>T) is ultra-rare (popmax 0.0321%, afr) (gnomAD).

What do computational predictors say about PFAS p.Pro617Ser (c.1849C>T)?

AlphaMissense predicts likely benign (score 0.0632) — an in-silico prediction, not a clinical call.

PFAS p.Pro617Ser

c.1849C>T · rs149123626 · VCV2465799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0632 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0321%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0632	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.17	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 0.25	GERP -3.6
Regional constraint	o/e 0.86	unconstrained · MANE · 5,370 bp · p 1.2e-05 · regional, not allelic
Overall
CADD	5.149	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 0.0321% African / African-American · 24/74,840 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00428% 69/1,613,700 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0321%	3,118
European (non-Finnish)	0.00373%	26,815
South Asian	0.0011%	91,084

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.Pro617Ser
Coding: c.1849C>T
MANE Select: NM_012393
dbSNP: rs149123626
Type: single nucleotide variant
Location: chr17:8264269 (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-pro617ser (accessed [today's date]).

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